Non-cryogenic, ammonia-free reduction of aryl compounds

ABSTRACT

A method of reducing an aromatic ring or a cyclic, allylic ether in a compound includes preparing a reaction mixture including a compound including an aromatic moiety or a cyclic, allylic ether moiety, an alkali metal, and either ethylenediamine, diethylenetriamine, triethylenetetramine, or a combination thereof, in an ether solvent; and reacting the reaction mixture at from −20° C. to 30° C. for a time sufficient to reduce a double bond in the aromatic moiety to a single bond or to reduce the cyclic, allylic ether moiety.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.63/080,205, filed Sep. 18, 2020, the disclosure of which is herebyincorporated by reference in its entirety.

The present disclosure is, in general, directed to methods of reducingan aromatic ring or a cyclic, allylic ether in a compound.

Dearomatization is an important platform in chemistry and drugdevelopment. The Birch reduction uniquely dearomatizes arenes into1,4-cyclohexadienes. (See, e.g., Birch, A. J. The Birch reduction inorganic synthesis. Pure Appl. Chem., 1996, 68, 553-556). In many cases,all the carbons of Birch reduction products could be differentiallyderivatized, providing useful building blocks for complex moleculesynthesis. Despite substantial efforts devoted to avoiding ammonia andcryogenic conditions, the traditional, cumbersome, and dangerousprocedure remains the standard.

The setup requires an alkali metal (either lithium, sodium, orpotassium), liquid ammonia (boiling point: −33° C.), and cryogenictemperature (≤−33° C.), e.g.,

One of the most tedious steps in setting up a Birch reduction is toaccumulate liquid ammonia from gaseous ammonia, which can take hours todays. The dissipation of ammonia after the reaction is complete can alsotake hours. These logistical challenges make it difficult to performmultiple Birch reductions in parallel.

To overcome these challenges, researchers have developed ammonia-freeconditions. For example, some have used neat ethylamine orethylenediamine and lithium, e.g.,

providing a mixture of over-reduced products (See, e.g., Benkeser R. A.et al. Reduction of organic compounds by lithium in low molecular weightamines. III. Reduction of aromatic compounds containing functionalgroups. J. Am. Chem. Soc., 1955, 77, 6042-6045 and Benkeser R. A. et al.Reduction of organic compounds by lithium in low molecular weightamines. I. Selective reduction of aromatic hydrocarbons to monoolefins.J. Am. Chem. Soc., 1955, 77, 3230-3233).

Some have reported the reduction of electron-deficient arenes andheterocycles using di-tert-butylbiphenyl($1000/mol) and lithium at −78°C., e.g.,

(See, e.g., Donohue T. J. et al. Ammonia free partial reduction ofaromatic compounds using lithium di-tert-butylbiphenyl (LiDBB), J. Org.Chem., 2002, 67, 5015-5018). This method was highly oxygen-sensitive andas lengthy as the standard Birch procedure (See, e.g., Donohue, T. J. etal., The partial reduction of electron-deficient pyrroles: proceduresdescribing both Birch (Li/NH₃) and ammonia-free (Li/DBB) conditions.Nat. Protoc., 2007, 2, 1888-1895).

Others have developed a novel protocol for the Birch reduction whichrequires 3-9 equivalents of 15-crown-5 ($1579/mol) and is limited toelectron-rich or neutral substrates, e.g.,

(See, e.g., Lei, P. et al. A practical and chemoselective ammonia-freeBirch reduction. Org. Lett., 2018, 20, 3439-3442).

Some have described an electrochemical reduction of electron-richarenes, which required 3.5-10 equivalents oftri(pyrrolidin-1-yl)phosphine oxide ($5,040/mol) and 3.0 equivalents of1,3-dimethylurea ($5.16/mol), e.g.,

both of which must be removed from the product by column chromatography.Their 0.45-mole scale reaction took 3 days in a flow reactor. Othersused a vicinal diamine and lithium at −10° C. to transform anisoles intophenols rather than 1,4-cyclohexadienes (See, e.g., Shindo, T. et al.Scope and limitations of lithium-ethylenediamine-THF-mediated cleavageat the α-position of aromatics: Deprotection of aryl methyl ethers andbenzyl ethers under mild conditions. Synthesis, 2004, 692-700). Finally,others treated arenes with lithium and ethylenediamine in THF or diethylether but did not isolate 1,4-cyclohexadiene products and indicated thatTHF might be a ligand for a lithium ion (see, e.g., Shindo, T. et al.Scope and limitations of lithium-ethylenediamine-THF-mediated cleavageat the α-position of aromatics: Deprotection of aryl methyl ethers andbenzyl ethers under mild conditions. Synthesis, 2004, 692-700 andHiraoka, C. et al. Screening, substrate specificity andstereoselectivity of yeast strains, which reduce sterically hinderedisopropyl ketones. Tetrahedron: Asymmetry, 2006, 17, 3358-3367).

It is noted that, as used in the preceding descriptions, DBB is4,4′-di-tert-butylbiphenyl; TPPA is tri(pyrrolidin-1-yl)phosphine oxide;and DMU is 1,3-dimethylurea.

Despite these efforts, the original, cumbersome and dangerous Birchprotocol remains the current standard. Due to the inconvenientprocedure, Birch reductions are often avoided in favor of more familiar,often less satisfactory, techniques (See, e.g., Huang, D. et al.Scalable procedure for the fragmentation of hydroperoxides mediated bycopper and iron tetrafluoroborate salts. Org. Biomol. Chem., 2016, 14,6197-6200 and Harvey, R. G. Metal-ammonia reduction of aromaticmolecules. Synthesis, 1970, 1970, 161-172). Therefore, there remains aneed for a Birch-type reduction that is fast and effective for bothelectron-rich and deficient arenes without ammonia, specializedequipment, or expensive additives.

STATEMENT REGARDING FEDERAL FUNDING

This invention was made with government support under Grant No. 1506942awarded by the National Science Foundation. The government has certainrights in the invention.

SUMMARY

A method of reducing an aromatic ring or a cyclic, allylic ether in acompound is provided. The method comprises:

-   -   preparing a reaction mixture comprising a compound comprising an        aromatic moiety or a cyclic, allylic ether moiety, an alkali        metal, and either ethylenediamine, diethylenetriamine,        triethylenetetramine, or a combination thereof, in an ether        solvent; and    -   reacting the reaction mixture at from −20° C. to 30° C. for a        time sufficient to reduce a double bond in the aromatic moiety        to a single bond or to reduce the cyclic, allylic ether moiety.

Also provided herein is a method of reducing an aromatic ring or acyclic, allylic ether in a compound, comprising:

-   -   preparing a reaction mixture comprising a compound comprising an        aromatic moiety or a cyclic, allylic ether moiety, an alkali        metal, an alcohol, and either ethylenediamine,        diethylenetriamine or a combination thereof, in an ether        solvent; and    -   reacting the reaction mixture at from −20° C. to 30° C. for a        time sufficient to reduce a double bond in the aromatic moiety        to a single bond or to reduce the cyclic, allylic ether moiety.

The following numbered clauses provide various aspects or embodiments ofthe present invention.

Clause 1. A method of reducing an aromatic ring or a cyclic, allylicether in a compound, comprising:

-   -   preparing a reaction mixture comprising a compound comprising an        aromatic moiety or a cyclic, allylic ether moiety, an alkali        metal, and either ethylenediamine or diethylenetriamine, in an        ether solvent; and    -   reacting the reaction mixture at from −20° C. to 30° C. for a        time sufficient to reduce a double bond in the aromatic moiety        to a single bond or to reduce the cyclic, allylic ether moiety.

Clause 2. The method of clause 1, wherein the aromatic moiety issubstituted with a C₁-C₆ carboxylic acid, such as carboxyl (e.g. benzoicacid), carboxymethy, carboxyethyl, carboxypropyl, carboxybutyl,carboxypentyl, or carboxyhexyl, including structural isomers thereof.

Clause 3. A method of reducing an aromatic ring or a cyclic, allylicether in a compound, comprising:

-   -   preparing a reaction mixture comprising a compound comprising an        aromatic moiety or a cyclic, allylic ether moiety, an alkali        metal, an alcohol, and either ethylenediamine or        diethylenetriamine, in an ether solvent; and    -   reacting the reaction mixture at from −20° C. to 30° C. for a        time sufficient to reduce a double bond in the aromatic moiety        to a single bond or to reduce the cyclic, allylic ether moiety.

Clause 4. The method of clause 3, wherein the compound comprising anaromatic moiety is n-butyl phenyl ether.

Clause 5. The method of clause 3, wherein the alcohol is a C₂-C₆ alkylalcohol (e.g. alkanol), such as ethanol, a propanol, a butanol, apentanol, or a hexanol.

Clause 6. The method of any one of clause 4 or 5, wherein the alcohol isa secondary or tertiary alcohol.

Clause 7. The method of any one of clauses 1-6, wherein the alkali metalis Li.

Clause 8. The method of any one of clauses 1-7, wherein the aromaticmoiety is a phenyl moiety or a fused benzene ring of a polycyclicaromatic moiety.

Clause 9. The method of any one of clauses 1-7, wherein the aromaticmoiety is C₆-aryl or substituted C₆-aryl.

Clause 10. The method of any one of clauses 1-9, wherein the aromaticmoiety is substituted with a C₁-C₆ carboxylic acid, such as carboxyl(e.g. benzoic acid), carboxymethy, carboxyethyl, carboxypropyl,carboxybutyl, carboxypentyl, or carboxyhexyl, including structuralisomers thereof.

Clause 11. The method of any one of clauses 1-9, wherein the aromaticmoiety is substituted with a C₁-C₆ alkoxyl group, such as methoxyl,propoxyl, butoxyl, pentyloxyl, or hexyloxyl, including structuralisomers thereof.

Clause 12. The method of any one of clauses 1-9, wherein the aromaticmoiety is a carbonyl-substituted C₁-C₆ alkyl group (e.g., C₁-C₆ alkylketones or aldehydes), including structural isomers thereof.

Clause 13. The method of any one of clauses 1-12, wherein the reactionis performed for a length of time sufficient to yield at least 50% yieldof the product of the conversion of the double bond in the aromaticmoiety to a single bond.

Clause 14. The method of clause 1, wherein the compound is benzoic acid,a benzylic alcohol, or a free amine.

Clause 15. The method of any one of clauses 1-14, wherein the ethersolvent is a saturated cyclic ether, such as tetrahydrofuran or aderivative thereof, or 1,4, dioxane, or a derivative thereof, where thederivative optionally can be alkyl-substituted or halo-substituted.

Clause 16. The method of any one of clauses 1-15, wherein theethylenediamine:compound molar ratio or the diethylenetriamine:compoundmolar ratio in the reaction mixture ranges from 2-20:1.

Clause 17. The method of any one of clauses 1-16, wherein the alkalinemetal:compound molar ratio in the reaction mixture ranges from 2-10:1.

Clause 18. The method of any one of clauses 1-16, wherein theethylenediamine:alkaline metal molar ratio, such as theethylenediamine:Li molar ratio, or the diethylenetriamine:alkaline metalmolar ratio, such as the diethylenetriamine:Li molar ratio isapproximately or about 2:1.

Clause 19. The method of any one of clauses 1-18, wherein the reactionmixture is reacted at a temperature ranging from −20° C. to 30° C.

Clause 20. The method of any one of clauses 1-18, wherein the reactionmixture is reacted at a temperature ranging from approximately 0° C. to10° C.

Clause 21. The method of any one of clauses 1-18, wherein the reactionmixture is reacted at approximately 0° C.

Clause 22. The method of any one of clauses 1-21, wherein the compoundcomprises an aromatic moiety.

Clause 23. The method of any one of clauses 1-22, wherein the compoundcomprises a cyclic, allylic ether moiety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the % yield diene 4 and over-reduced product5 at different stirring times for different starting concentrations ofn-butyl phenyl ether 3;

FIG. 2 is a graph depicting the % yield of diene 2 at different stirringtimes for different concentrations of benzoic acid 1;

FIG. 3 is a chart of the non-limiting amine ligands acceptable for thereduction of benzoic acid 1 and n-butyl phenyl ether 2;

FIG. 4 is a schematic of normal chemoselectivity with ethylenediamine L1and reversed chemoselectivity with triethylenetetramine L4;

FIG. 5A is a graph depicting the % yield of diene 4 in the reduction ofn-butyl phenyl ether 3 at different stirring times for different levelsof THF;

FIG. 5B is a graph depicting the % yield of diene 2 in the reduction ofbenzoic acid 1 at different stirring times for different levels of THF;

FIG. 5C is a graph depicting the % yield of diene 4 in the reduction ofn-butyl phenyl ether 3 at different stirring times for differentethereal solvents;

FIG. 5D is a graph depicting the % yield of diene 2 in the reduction ofbenzoic acid 1 at different stirring times for different etherealsolvents;

FIG. 5E is a graph depicting the % yield of diene 4 in the reduction ofn-butyl phenyl ether 3 at different stirring times for different amineligands;

FIG. 5F is a graph depicting the % yield of diene 2 in the reduction ofbenzoic acid 1 at different stirring times for different amine ligands;

FIG. 5G is a graph depicting the % yield of diene 4 in the reduction ofn-butyl phenyl ether 3 at different stirring times for different ratiosof ethylenediamine L1 to lithium;

FIG. 5H is a graph depicting the % yield of diene 2 in the reduction ofbenzoic acid 1 at different stirring times for different ratios ofethylenediamine L1 to lithium;

FIG. 6A is a graph depicting the % yield of diene 4 in the reduction ofn-butyl phenyl ether 3 at different stirring times for differentequivalences of n-butyl phenyl ether 3; and

FIG. 6B is a graph depicting the % yield per minute of diene 4 in thereduction of n-butyl phenyl ether 3 for different equivalences ofn-butyl phenyl ether 3.

DETAILED DESCRIPTION

The use of numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges are both preceded by the word “about”. In this manner,slight variations above and below the stated ranges can be used toachieve substantially the same results as values within the ranges.Also, unless indicated otherwise, the disclosure of ranges is intendedas a continuous range including every value between the minimum andmaximum values. As used herein “a” and “an” refer to one or more.

As used herein, the term “comprising” is open-ended and may besynonymous with “including”, “containing”, or “characterized by”. Theterm “consisting essentially of” limits the scope of a claim to thespecified materials or steps and those that do not materially affectbasic and novel characteristic(s). The term “consisting of” excludes anyelement, step, or ingredient not specified in the claim. As used herein,embodiments “comprising” one or more stated elements or steps alsoinclude, but are not limited to embodiments “consisting essentially of”and “consisting of” these stated elements or steps.

The methods described herein can be used for the reduction of anaromatic moiety, e.g., aromatic rings, or an allylic ether moiety toproduce, e.g., unconjugated dihydro derivatives. The reaction may beconducted in an ether solvent at a temperature in the range of from −20°C. to 30° C., for example from −20° C. to 30° C., such as from 0° C. to10° C. The reaction may be conducted for a length of time to reduce adouble bond in a reaction mixture comprising a compound (substrate)comprising an aromatic moiety or a cyclic, allylic ether moiety. Thereaction is typically conducted for a length of time to convert thearomatic moiety or the cyclic, allylic ether moiety with at least atleast 50%, at least 60%, at least 70%, at least 80%, at least 90%, or atleast 99% molar conversion rate, including any increment therebetween,for reducing a double bond of the compound comprising an aromatic moietyor a cyclic, allylic ether moiety. The length of time for the reactionmay be at least 1 minute, at least 5 minutes, at least 15 minutes, atleast 30 minutes, at least 45 minutes, or at least 60 minutes, orlonger, such as for 15, 30, 45, 60, 90, or 120 minutes.

The reaction may be performed in the presence of an alkali metal, suchas Li, K, or Na, in the presence of ethylenediamine. The substrate canbe any substrate comprising an aromatic group suitable for reduction byBirch reduction or a cyclic, allylic ether. The aromatic group or thecyclic, allylic ether group may be substituted. By “substituted” it ismeant that one or more hydrogen atoms of the aromatic group issubstituted with another group (“substituents”), such as an alkyl,alkoxyl (ether), carbonyl, carboxyl, nitrate, sulfate, or other groups.While carboxyl-containing substituents may react robustly without thepresence of an alcohol in the reaction mixture, certain groups mayrequire the presence of an alcohol, such as a secondary or tertiaryalcohol, for the reaction to proceed in a reasonable pace. For example,as shown below, reduction of benzoic acid (carboxyl-substituted) did notrequire an alcohol to be present for the reaction to proceed in asuitably robust manner, while reduction of reduction of n-butyl phenylether (butoxyl substituted), having an alkoxyl (ether) substitution,required an alcohol for the reaction to proceed with good yield, andwith secondary or tertiary alcohols, such as isopropyl alcohol, t-butylalcohol, and t-amyl alcohol, providing greater yields. The substrate maybe a benzylic alcohol. A “benzylic alcohol” refers to an aromaticcompound that comprises a pendant alcohol (—OH) group. The substrate maybe a free amine. A “free amine” refers to a compound that comprises anamine functional group that is not protonated.

An aromatic (aryl) compound comprises an aromatic ring meeting therequirements of Hückel's rule, having 4n+2 π electrons in a conjugatedsystem of p orbitals, where n is an integer. The quintessential aromaticcompound being benzene. “Aryl,” alone or in combination refers to anaromatic ring system such as phenyl or naphthyl. Multi-ring structurescan be aromatic, such as anthracene, phenanthrene, or pyrene, as well asheterocyclic aromatic compounds, comprising one or more hetero-atoms,such as N, O, or S in place of a ring carbon, such as pyridine, pyrrole,furan, and thiophene. “Aryl” also can include aromatic ring systems thatare optionally fused with a cycloalkyl ring. A “substituted aryl” is anaryl that is independently substituted with one or more substituentsattached at any available atom to produce a stable compound, wherein thesubstituents can be as described herein. The substituents can be, forexample and without limitation, hydrocarbyl groups, alkyl groups, alkoxygroups, carboxyl-containing groups, ethers, and nitrate-containinggroups. “Optionally substituted aryl” refers to aryl or substitutedaryl. An aryloxy group can be, for example, an oxygen atom substitutedwith any aryl group, such as phenoxy. An arylalkoxy group can be, forexample, an oxygen atom substituted with any aralkyl group, such asbenzyloxy. “Arylene” denotes divalent aryl, and “substituted arylene”refers to divalent substituted aryl. “Optionally substituted arylene”refers to arylene or substituted arylene. A “polycyclic aryl group” andrelated terms, such as “polycyclic aromatic group” refers to a groupcomposed of at least two fused aromatic rings. “Heteroaryl” or“hetero-substituted aryl” refers to an aryl group substituted with oneor more heteroatoms, such as N, O, P, and/or S.

As used herein, “alkyl” refers to straight, branched chain, or cyclichydrocarbon groups including, for example, from 1 to about 20 carbonatoms, for example and without limitation C₁₋₃, C₁₋₆, C₁₋₁₀ groups, forexample and without limitation, straight, branched chain alkyl groupssuch as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, and the like. An alkyl group can be, forexample, a C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄,C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇, C₂₈,C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁, C₄₂,C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that is substituted orunsubstituted. Non-limiting examples of straight alkyl groups includemethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, anddecyl. Branched alkyl groups comprises any straight alkyl groupsubstituted with any number of alkyl groups. Non-limiting examples ofbranched alkyl groups include isopropyl, isobutyl, sec-butyl, andt-butyl. Non-limiting examples of cyclic alkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, andcyclooctyl groups. Cyclic alkyl groups also comprise fused-, bridged-,and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A“fused-” cyclic alkyl group refers to at least two cyclic groups thatshare two carbon atoms which are directly bonded with each other. A“spiro-” cyclic alky group refers to at least two cyclic groups thatshare one carbon atom. A “bridged-” cyclic alkyl group refers to atleast two cyclic groups that share two carbon atoms which are connectedby at least one additional carbon atom, forming a “bridge”. A cyclicalkyl group can be substituted with any number of straight, branched, orcyclic alkyl groups. “Substituted alkyl” can include alkyl substitutedat 1 or more (e.g., 1, 2, 3, 4, 5, or even 6) positions, whichsubstituents are attached at any available atom to produce a stablecompound, with substitution as described herein. “Optionally substitutedalkyl” refers to alkyl or substituted alkyl. “Alkylene” and “substitutedalkylene” can include divalent alkyl and divalent substituted alkyl,respectively, including, without limitation, methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,hepamethylene, octamethylene, nona methylene, or decamethylene.“Optionally substituted alkylene” can include alkylene or substitutedalkylene.

“Alkene or alkenyl” can include straight, branched chain, or cyclichydrocarbyl groups including, e.g., from 2 to about 20 carbon atoms,such as, without limitation C₂₋₃, C₂₋₆, C₂₋₁₀ groups having one or more,e.g., 1, 2, 3, 4, or 5, carbon-to-carbon double bonds. The olefin orolefins of an alkenyl group can be, for example, E, Z, cis, trans,terminal, or exo-methylene. An alkenyl or alkenylene group can be, forexample, a C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅,C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇, C₂₈, C₂₉,C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁, C₄₂, C₄₃,C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that is substituted orunsubstituted. “Substituted alkene” can include alkene substituted at 1or more, e.g., 1, 2, 3, 4, or 5 positions, which substituents areattached at any available atom to produce a stable compound, withsubstitution as described herein. “Optionally substituted alkene” caninclude alkene or substituted alkene. Likewise, “alkenylene” can referto divalent alkene. Examples of alkenylene include without limitation,ethenylene (—CH═CH—) and all stereoisomeric and conformational isomericforms thereof. “Substituted alkenylene” can refer to divalentsubstituted alkene. “Optionally substituted alkenylene” can refer toalkenylene or substituted alkenylene.

The term “alkoxy” can refer to an —O-alkyl group having the indicatednumber of carbon atoms. An ether or an ether group comprises an alkoxygroup. For example, a (C₁-C₆)alkoxy group includes —O-methyl (methoxy),—O-ethyl (ethoxy), —O-propyl (propoxy), —O-isopropyl (isopropoxy),—O-butyl (butoxy), —O-sec-butyl (sec-butoxy), —O-tert-butyl(tert-butoxy), —O-pentyl (pentoxy), —O-isopentyl (isopentoxy),—O-neopentyl (neopentoxy), —O-hexyl (hexyloxy), —O-isohexyl(isohexyloxy), and —O-neohexyl (neohexyloxy). “Hydroxyalkyl” refers to a(C₁-C₁₀)alkyl group wherein one or more of the alkyl group's hydrogenatoms is replaced with an —OH group. Examples of hydroxyalkyl groupsinclude, but are not limited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂CH₂OH, and branchedversions thereof. The term “ether” or “oxygen ether” refers to an alkylgroup wherein one or more of the alkyl group's carbon atoms is replacedwith an —O— group. The term ether can include —CH₂—(OCH₂—CH₂)_(q)OP₁compounds where P₁ is a protecting group, —H, or a (C₁-C₁₀)alkyl.Exemplary ethers include polyethylene glycol, diethylether, methylhexylether and the like.

“Carboxyl” or “carboxylic” refers to group having an indicated number ofcarbon atoms, where indicated, and terminating in a —C(O)OH group, thushaving the structure —R—C(O)OH, where R is an unsubstituted orsubstituted divalent organic group that can include linear, branched, orcyclic hydrocarbons. Non-limiting examples of these include: C₁₋₈carboxylic groups, such as ethanoic, propanoic, 2-methylpropanoic,butanoic, 2,2-dimethylpropanoic, pentanoic, etc. “Amine” or “amino”refers to group having the indicated number of carbon atoms, whereindicated, and terminating in a —NH₂ group, thus having the structure—R—NH₂, where R is a unsubstituted or substituted divalent organic groupthat, e.g. includes linear, branched, or cyclic hydrocarbons, andoptionally comprises one or more heteroatoms. The term “alkylamino”refers to a radical of the formula —NHRx or —NRxRx where each Rx is,independently, an alkyl radical as defined above.

An alcohol is an organic compound that carries at least one hydroxylfunctional group (—OH) bound to a saturated carbon atom. Compounds withmore than one hydroxyl functional group may be referred to as polyols.An alcohol may be classified by the number of carbons attached to thecarbon to which the hydroxyl group is connected. In a primary alcohol,carbon atom that carries the —OH group is only attached to one alkylgroup. In a secondary (2°, sec-, or s-) alcohol, the carbon atom withthe —OH group attached is joined directly to two alkyl groups, which maybe the same or different. In a tertiary (3°, tert-, or t-) alcohol, thecarbon atom holding the —OH group is attached directly to three alkylgroups, which may be the same or different in any combination. Examplesof primary alcohols include, without limitation, n-propyl alcohol,ethanol, and 2-methylpropan-1-ol. Examples of secondary alcoholsinclude, without limitation, isopropyl alcohol, butan-2-ol, pent-3-ol,and cyclohexanol. Examples of tertiary alcohols include, withoutlimitation, t-butyl alcohol and t-amyl alcohol.

Terms combining the foregoing refer to any suitable combination of theforegoing, such as arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl,heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl,alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl,alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl,alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl,alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl,alkenylheteroarylalkenyl, alkenylheteroarylalkynyl,alkynylheteroarylalkyl, alkynylheteroarylalkenyl,alkynylheteroarylalkynyl, alkylheterocyclylalkyl,alkylheterocyclylalkenyl, alkylhererocyclylalkynyl,alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl,alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl,alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl,alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl,alkynylhereroaryl. As an example, “arylalkylene” refers to a divalentalkylene wherein one or more hydrogen atoms in an alkylene group isreplaced by an aryl group, such as a (C₃-C₈)aryl group. Examples of(C₃-C₈)aryl-(C₁-C₆)alkylene groups may include without limitation1-phenylbutylene, phenyl-2-butylene, 1-phenyl-2-methylpropylene,phenylmethylene, phenylpropylene, and naphthylethylene. The term“(C₃-C₈)cycloalkyl-(C₁-C₆)alkylene” refers to a divalent alkylenewherein one or more hydrogen atoms in the C₁-C₆ alkylene group isreplaced by a (C₃-C₈)cycloalkyl group. Examples of(C₃-C₈)cycloalkyl-(C₁-C₆)alkylene groups may include without limitation1-cycloproylbutylene, cycloproyl-2-butylene,cyclopentyl-1-phenyl-2-methylpropylene, cyclobutylmethylene andcyclohexylpropylene.

“Carbonyl” refers to the —C(O)— moiety within a substituent, such as aalkyl substituent on an aromatic ring, thereby forming a ketone oraldehyde substituent.

“Heteroatom” refers to any atom other than carbon or hydrogen, forexample, N, O, P and S. Compounds that contain N or S atoms may beoxidized to the corresponding N-oxide, sulfoxide or sulfone compounds.“Hetero-substituted” refers to an organic compound in any embodimentdescribed herein in which one or more carbon atoms are substituted withany atom other than carbon or hydrogen, for example, N, O, P or S.

A cyclic, allylic ether group or moiety is an optionally substitutedalkyl ring that is hetero-substituted with an oxygen, and including asingle carbon-to-carbon double bond (allylic moiety) in the ring.Non-limiting examples of such cyclic, allylic ether group or moietyinclude dihydro pyranly or dihydrofuranyl groups or moieties.

The reaction described herein may be conducted in any suitable solventthat permits the reaction to proceed. The solvent may be a saturatedether solvent which is a hetero-substituted alkane, comprising one ormore oxygen hetero atoms. Non-limiting examples of saturated ethercompounds include dialkyl ethers, such as, without limitation, dimethylether, diethyl ether, diisopropyl ether, dibutyl ether, etc., andcyclical oxygen hetero-substituted alkanes, such as tetrahydrofuran and1,4-dioxane. The saturated ether solvent may be substituted, such aswith alkyl groups.

The reactions described herein may include an alkali metal. Alkalimetals may include Li, K, or Na. For example, the reactions describedherein may include an alkali metal including Li.

EXAMPLES

A Birch reduction promoted by polyamines and lithium in tetrahydrofuranat ambient temperature is provided. This method is easy to set up,inexpensive, scalable, time economical, accessible to any chemicallaboratory, and capable of reducing a wide range of substrates.Importantly, the Birch reduction can be combined with organocupratechemistry for the first time. Inner- and outer-sphere electron transferprocesses may account for the inverse electron-demand reduction ofarenes. Polyamines and t-butanol render the chemoselectivity and productselectivity of reductions tunable, making previously unattainablematerials accessible.

For example, and without limitation, such a Birch reduction can includeethylenediamine as a ligand ($2.67/mol) and lithium in THF, e.g.,

The relationship between ligand-structure-reactivity revealed newchemoselectivity. In the above example, ^(t)BuOH was used to controlproduct selectivity. Ethylenediamine ($2.67/mol can be removed byextraction. A broader scope was found of the electrophile (E) withcopper (Cu). Sterics, linker length, and denticity (e.g.,

may all be investigated to improve the overall reaction. The tunabilityof polyamines for the reduction, including unprecedented inverseelectron-demand chemoselectivity, was reported. Finally, more activeroles for amines and alcohols than previously considered, providing aplatform for controlling the chemoselectivity, is proposed.

Ammonia gas in a balloon and various amine-based ligands were tested fortheir suitability in the reaction of benzoic acid 1 to form a diene 2,in the following reaction:

The results of these tests, described hereinafter, are shown in Table 1,below. Benzoic acid (PhCO₂H) 1 was chosen as the starting modelsubstrate because of the deficiency of currently reported conditions forthe reduction of electron-deficient arenes. First, a protocol withammonia gas in a balloon (See, e.g., Altundas, A. et al. Excellent andconvenient procedures for reduction of benzene and its derivatives.Turk. J. Chem., 2005, 29, 513-518) to find that diene 2 was obtained in83% yield was evaluated (Entry 1). However, this method was noteffective for electron-rich substrates, typically resulting inincomplete reactions. Consequently, alternative amine-based ligands wereinvestigated that could be broadly applicable, inexpensive, and easy tohandle while affording the desired Birch reduction products. With 1.0equivalent of ethylenediamine L1

diene 2 was produced in 4% yield (Entry 2). Using 2.5 equivalents of L1improved the yield to 83% (Entry 3). Using more L1 could reduce theamount of lithium and the time (90% yield, Entry 4).

The reaction did not proceed without L1 (Entry 5). Also, the combinationof 1,2-diamine L1 and lithium was essential as there was no reductionwhen sodium metal was employed (Entry 6). It was then investigatedwhether the reaction could be improved further by fine-tuning the linkerlength and denticity of the ligand. 1,3-Diamine L2

gave no product (Entry 7). Diethylenetriamine L3

was as effective as L1, providing diene 2 in 86% yield (Entry 8), buttriethylenetetramine L4

was ineffective (Entry 9). Other 1,2-diamines L5-L8 (where L5 is

with R¹═R²═H, L6 is

with R¹═H and R²=methyl group, L7 is the cis isomer of

and L8 is the trans isomer of

failed to promote the reduction (Entries 10-13). While L9

with R═H, had similar reactivity as L1, affording diene 2 in 85% yield(Entry 14), the reaction did not progress with L10, (e.g.,

with R=methyl group (Entry 15). Although triamine L3 successfullyreduced PhCO₂H 1 to diene 2, L1 was continued to be used (L1: $2.67/molvs L3: $7.59/mol). Further, no reduction occurred with cyclic amine L12,

(Entry 16). The reaction could be scaled up to an 82-mmol scale,resulting in 95% isolated yield (Entry 17).

TABLE 1 The Birch reduction of PhCO₂H 1^(a) Entry X Amine Y Time (h)Yield (%)^(b)  1^(c) 5.0 NH₃ 8   83^(c) in balloon 2 5.0 L1 1.0 6  4 35.0 L1 2.5 6 83 4 2.5 L1 5.0 1 90 5 2.5 None 1  0  6^(d) 3.0 L1 6.0 1  07 2.5 L2 5.0 1  0 8 2.5 L3 5.0 1 86 9 3.0 L4 6.0 1  0 10  2.5 L5 5.0 1 0 11  2.5 L6 5.0 1  0 12  2.5 L7 5.0 1  0 13  2.5 L8 5.0 1  0 14  3.0L9 6.0 1 85 15  3.0 L10 6.0 1 <5 16  3.0 L12 6.0 1  0 17^(e) 3.0 L1 6.01  95^(f) ^(a)All reactions performed on a 4.0-mmol scale unlessotherwise noted. ^(b)Yield determined by ¹H NMR using1-methoxyadamantane as an internal standard. ^(c)400-mmol scale. 0 to25° C. ^(d)Sodium metal used instead of lithium. ^(e)82-mmol scale andincreased equivalencies. ^(f)Isolated yield.

Next, the reaction conditions for an electron-rich system usingn-butoxybenzene (^(n)BuOPh) 3 as a model substrate were optimized forthe following reaction:

This substrate was not reduced without alcohol present (Entry 18). Thissubstrate was not reduced without alcohol present (Table S2, entry 1).This is consistent with the known mechanism in which electron-richarenes cannot accept the second electron unless the radical anionintermediate is protonated to form the corresponding radical species(see, for example, Rabideau, P. W. The metal-ammnia reduction ofaromatic compounds. Tetrahedron 1989, 45, 1579-1603). Also, we did notobserve any of the dealkylated phenol byproduct that was reported in themethod developed in Shindo, T. et al. Scope and limitations oflithium-ethylenediamine-THF-mediated cleavage at the α-position ofaromatics: Deprotection of aryl methyl ethers and benzyl ethers undermild conditions Synthesis, 2004, 692-700. With methanol, ethanol,isopropanol, t-butanol, and t-amyl alcohol, diene 4 was produced in 33,58, 62, 75, and 68% yield, respectively, with the over-reduced product 5in 4-11% yield (Entries 19-23). To study the importance of the acidityof the alcohol, 2,2,2-trifluoroethanol and1,1,1,3,3,3-hexafluoroisopropanol were tested, which afforded yields of52 and 26%, respectively (Entries 24 and 25). Use of 1,3-diamine L2 andtriamine L3 diminished yields to 33 and 9%, respectively (Entries 26 and27). Interestingly, the yield was increased to 51% with tetramine L4(Entry 28; cf. Entry 26). The reaction did not proceed when sodium wasused in lieu of lithium (Entry 29). With L5, L6 or L11

with R¹=methyl group and R²═H), diene 4 was produced in 33, 3, and 27%yield, respectively (Entries 30-32). When employing cyclic amine L12, noreduction occurred (Entry 33). Interestingly, trans diamine L7 wasineffective even after 3 h (Entry 34), and cis diamine L8 promoted thereduction albeit more slowly than L1 (Entries 35 and 36). Use ofdiamines L9 and L10 produced diene 4 in 65% and 11% (Entries 37 and 38).To fully consume the starting material, the equivalents of lithium andL1 were increased (Entry 39).

TABLE 2 The Birch reduction of ^(n)BuOPh 3^(g) % % % % En- A- yield^(b)yield^(b) En- A- yield^(b) yield^(b) try mine ROH 4 5 try mine ROH 4 518 L1 none 0 0 29^(d) L1 ^(t)BuOH 0 0 19 L1 MeOH 33 4 30 L5 ^(t)BuOH 33ND^(k) 20 L1 EtOH 58 9 31 L6 ^(t)BuOH 3 ND 21 L1 ^(i)PrOH 62 8 32 L11^(t)BuOH 27 ND 22 L1 ^(t)BuOH 75 11 33^(h) L12 ^(t)BuOH 0 0 23 L1t-amyl- 68 8 34^(i) L7 ^(t)BuOH 0 ND OH 24 L1 TFE 52 7 35 L8 ^(t)BuOH 11ND 25 L1 HFIP 26 3 36^(i) L8 ^(t)BuOH 73 ND 26 L2 ^(t)BuOH 33 6 37^(j)L9 ^(t)BuOH 65 9 27 L3 ^(t)BuOH 9 1 38^(j) L10 ^(t)BuOH 11 3 28 L4^(t)BuOH 51 10 39^(h,j) L1 ^(t)BuOH 85 15 ^(g)All reactions run on a3.3-mmol scale unless otherwise noted. ^(h)2.5 equiv of ^(t)BuOH used.^(i)Reaction time was increased to 3 h. ^(j)3 equiv of lithium and 6equiv of L1 used. ^(k)ND = not determined.

Because the beginning of the reaction involves the dissolution of solidlithium, it was investigated if the stirring rate played a role andfound that the reaction proceeded faster at the greater stir rate, theresults of which are shown in Table 3 (Entry 29 vs Entry 30). In Entries29-31 in Table 3, n-butyl phenyl ether 3, 1,2-diamine L1, tert-butylalcohol, lithium, and THF were used. Although the Birch reductionproceeds through a radical anion intermediate, the use of distilled anddegassed THF only mildly improved the yield (Entry 31).

TABLE 3 The Birch reduction of n-butyl phenyl ether^(l) % % % % yieldyield % % Stir yield yield 10 10 yield^(b) yield^(b) Rate 5 min 5 minmin min 60 min 60 min Entry (RPM) 4 5 4 5 4 5 29 300 1 0 4 0 4 — 30 600— — 15 — 80 12 31^(m) 600 16 2 30 4 83 12 ^(l)All reactions run on a 3.3mmol scale unless otherwise noted. ^(m)With distilled and degassed THF.

To develop a more scalable procedure, it was important that the reactionbe performed at synthetically relevant concentrations. For Entries 32-35in Table 4, n-butyl phenyl ether 3, 1,2-diamine L1, tert-butyl alcohol,lithium, and THF were used. When n-butyl phenyl ether was used as asubstrate, its concentration had an effect on both the reaction rate andside product formation, as shown in Table 4, the results of which aregraphed in FIG. 1 . Specifically, when the concentration of the startingmaterial (SM) was above 0.4 M, both the yield of the desired product andreaction rate increased (Entries 32-35).

TABLE 4 The Birch reduction of n-butyl phenyl ether^(n) % % % % % % % %yield^(b) yield^(b) yield^(b) yield^(b) yield^(b) yield^(b) yield^(b)yield^(b) 10 10 15 15 60 60 [SM] 5 min 5 min min min min min min minEntry (M) 4 5 4 5 4 5 4 5 32 0.1 8 — 24 3 36 4 70 10 33 0.2 11 — 39 5 577 76 11 34 0.4 35 5 62 8 76 11 71 20 35 0.8 74 10 84 12 85 14  51^(o) 23^(n)All reactions were performed on a 20-mmol scale unless otherwisenoted. ^(o)1-OBu-1,3-cyclohexadiene formed in ~23% yield.

With benzoic acid, the reduction could be performed at 0.8 M withoutloss of yield, as shown in Table 5 (Entries 36-39), the results of whichare graphed in FIG. 2 . In Entries 36-39 of Table 5, benzoic acid 1,1,2-diamine L1, lithium, and THF were used.

TABLE 5 The Birch reduction of benzoic acid^(n) % % % yield^(b) %yield^(b) yield^(b) 45 yield^(b) [SM] 1 min 5 min min 60 min Entry (M) 22 2 2 36 0.1 0 11 53 61 37 0.2 22 47 85 97 38 0.4 48 77 83 99 39 0.8 7089 86 99

After optimization of butyl phenyl ether, the substrate scope ofelectron rich and neutral systems was explored. For the development ofscalable procedures, it would be desirable to perform the reaction athigher concentrations. It was found (see FIG. 6A) that the PhCO₂H and^(n)BuOPh concentrations could be increased up to 0.8 M, which alsoaccelerated the reduction. While the yield of diene 2 was unaffected,the increased reaction rate led to mono-olefin 5 and the1,3-cyclohexadiene 4 with ^(n)BuOPh 3 (see FIG. 6A). To further improvethe scalability, lithium was suspended in THF the flask was cooled onice, to which a solution of L1 and PhCO₂H in THF was added. Thisprocedure was equally effective when the reaction was scaled up to a0.50-mole scale. Monitoring the internal temperature revealed that thereaction proceeded at approximately 10° C.; therefore, it was decided tokeep the internal temperature in the 10-26° C. range. The 0.50-molescale reaction took 1 h including preparation and workup to obtain diene2 in 95% yield. A similar reverse-addition protocol was applied to both4-methyl anisole and 4-OTBS toluene. It was necessary to add t-butanolto the suspension last to suppress both the overreduction andisomerization of the desired product to the 1,3-cyclohexadiene. 4-Methylanisole was reduced to diene 22

with the methyl group in the 4 position) in a 68% yield, while 4-OTBStoluene (10-g scale) was reduced to diene 23, i.e.,

in a 76% yield. Both of these experiments (setup+reaction+isolation ofthe products) also took 1 h, which is substantially shorter than theknown art (1-2 days) (See, e.g., Peters, B. K. et al. Scalable and safesynthetic organic electroreduction inspired by Li-ion battery chemistry.Science, 2019, 363, 838-845). Also, it was found that the reactionproceeded faster with a greater stir rate. Finally, the current methodis compatible with trace water and air as the use of distilled anddegassed THF only mildly improved the yield (78% vs 75%).

Generally, electron-withdrawing groups increase reduction rates whileelectron-donating groups decrease them. Specifically, the Birchreduction of benzoate is more than 61 times faster than that of anisoleunder traditional conditions (See, e.g., Krapcho, A. P. et al. Kineticsof the metal-ammonia-alcohol reductions of benzene and substitutedbenzenes. J. Am. Chem. Soc., 1959, 81, 3658-3666). In FIG. 3 , theresults from the ligand screen in Tables 1 and 2 are summarized; in theleft, smaller rectangle are the ligands that reduced PhCO₂H while in theright, larger rectangle (which includes those ligands that reducedPhCO₂H) are the ligands that reduced ^(n)BuOPh. The summary suggestedthat it might be possible to reduce an electron-rich arene in preferenceto an electron-deficient arene. A reduction with an equimolar mixture ofPhCO₂H and ^(n)BuOPh, L1, and lithium without t-butanol was performed toobtain acid 2 and ether 4 in a 59 and 7% yield, respectively (see FIG. 4). The same conditions with t-butanol gave a mixture of acid 2 alongwith other intractable products. The earlier results were then exploitedby replacing L1 with tetramine L4 to discover that the electron-richarene ^(n)BuOPh was more reactive than the electron-deficient arenePhCO₂H (43% consumption of PhCO₂H vs. 85% consumption of ^(n)BuOPh),affording 2 and 4 in a 1:2 ratio.

The liquid ammonia solvent in the Birch reduction has hamperedleveraging the carbanion intermediate. For example, a Birch alkylationwith methyl vinyl ketone failed because ammonia caused thepolymerization of the ketone (See, e.g., Rao, G. S. R. S. et al. Michaelreactions of the anions generated by the metal-ammonia reduction ofbenzoic acids. J. Chem. Soc., Chem. Comm., 1980, 315-316). Given the useof only 6 equivalents of L1, it was hypothesized that the Birchreduction could be coupled with cuprate chemistry. After the reductionof PhCO₂H under these reaction conditions, CuI and methyl vinyl ketonewere added:

Under these unoptimized conditions, ketone 43 was generated in 20% yieldwhile forming a quaternary carbon.

The kinetics were then investigated for both ^(n)BuOPh and PhCO₂H undervarious conditions, as shown in FIGS. 5A-5H. First, it was found thatthe reduction rates depended upon THF concentrations, as well as thechoice of ethereal solvent (see FIGS. 5A-5D). The decreasing polarity ofthe reaction medium most likely affects the stability and solubility ofthe radical anion that is usually stabilized by ammonia (See, e.g.,Brezina, K. et al. Benzene radical anion in the context of the Birchreduction: When solvation is the key. J. Phys. Chem. Lett., 2020, 11,6032-6038). Next, as L1:lithium ratio increased (see FIGS. 5E and 5F) sodid the reaction rate (see FIGS. 5G and 5H). However, the reduction of^(n)BuOPh produced increasing amounts of 1-butoxy-1,3-cyclohexadiene 4as well as mono-olefin 5. This is similar to the results in which onlythe initial concentration of the reaction mixture was increased.

Finally, the reduction rate steadily increased when changing from 0equivalents to 2.5 equivalents of t-butanol. However, when increasingthe equivalents of t-butanol past 2.5, the reduction rate decreased (seeFIGS. 6A-6B).

From the data presented here, it is propose that the reduction of PhCO₂Hproceeds as follows:

first, lithium(0) is dissolved through the coordination of the amineligand and THF to create LiN-1. Second, an electron transfer occurs togive radical anion LiN-2. Subsequently, another electron transfer occursto afford trianion LiN-3, which may be in equilibrium with higher orderaggregates. Lastly, this species is protonated to form LiN-4.

The following shows our hypothesized mechanism for the reduction of^(n)BuOPh:

An electron is transferred from LiN-1 to the substrate to form radicalanion LiN-5. Next, t-butanol binds the lithium to give LiN-6, whichtriggers the rate-determining intramolecular protonation to form theradical species LiN-7. In both of these cases, the lithium dissolutionand electron transfer are in equilibrium.

To understand the ligand's impact on reactivity, the dissolution oflithium(0) was first considered. If the dissolution step accounts forthe structure-reactivity relationship, the effective amines shoulddissolve lithium faster than ineffective amines (FIG. 3 ). Thequalitative experiments with lithium and ethylenediamine, cis-, ortrans-1,2-diaminocyclohexane in THF without arenes showed that whileethylenediamine partially dissolved lithium, the other two amines didnot. This is distinct from the fast dissolution of lithium in thepresence of arene substrates. Therefore, dissolution alone cannotaccount for the structure-reactivity relationship.

Second, the imparct of the ligand structure on the electron transferprocesses were considered. It was reasoned that as the denticity of theligand increases from ethylenediamine to diethylenetriamine then totriethylenetetramine, the amino groups displace the benzoate of LiN-2with nitrogens, disrupting the electron transfer step, particularly ifthis is an inner-sphere electron transfer. Currently, it is unclear howmany nitrogen atoms are bound to lithium in each intermediate, but thefailure with cyclic amine L12 suggests that when four amino groups arebound, such a complex appears unreactive. Steric effects of amineswarrant further studies.

Third, the influence that amines have on the rate-determiningprotonation step for the reduction of ^(n)BuOPh was considered.Organolithum's carbon is protonated faster with 1,2-diamines than with1,3-diamines. Therefore, it is suggested that the protonations of LiN-3and LiN-6 are faster with ethylenediamine than with 1,3-diaminopropane.

Fourth, consideration was given to how the alcohol affects theprotonation and product distribution in the reduction. The alcohol mayplay a more significant role than only a proton donor. For example, ift-butanol intermolecularly protonates radical anion LiN-5, the rateshould be linearly proportional to the alcohol concentration. Instead,we observed a bell-shaped trend, indicating that protonation may occurintramolecularly through LiN-6. The slight preference between relatedsubstrates with different steric environments bodes well with thishypothesis. Importantly, the reaction mixture containing ^(n)BuOPhturned light blue with 8 equiv of t-butanol, although the desiredreduction did not occur. This suggests excess alcohol may outcompeteamino groups on the lithium at an earlier stage of the reaction, formingless reductive solvated electrons, similar to work with SmI₂ (See, e.g.,Shabangi, R. A. et al. Electrochemical investigation of the reducingpower of SmI₂ in THF and the effect of HMPA cosolvent. TetrahedronLett., 1997, 38, 1137-1140). A mass effect may have obscured theadditional role of t-butanol in the past; traditionally, the amine hasbeen used in greater excess than the alcohol, outcompeting the alcoholfor coordination to the lithium.

When less than 1 equiv of t-butanol was present in the reduction of^(n)BuOPh, the monoolefin was formed in ca. 20% yield. This is similarto the reduction without alcohol (See, e.g., Benkeser R. A. et al.Reduction of organic compounds by lithium in low molecular weightamines. III. Reduction of aromatic compounds containing functionalgroups. J. Am. Chem. Soc., 1955, 77, 6042-6045 and Benkeser R. A. et al.Reduction of organic compounds by lithium in low molecular weightamines. I. Selective reduction of aromatic hydrocarbons to monoolefins.J. Am. Chem. Soc., 1955, 77, 3230-3233). Although the addition of analcohol under the Benkeser-type conditions gave Birch-type products,these findings have not garnered widespread use. The alcohol isnecessary to synthesize Birch products by protonating both theorganolithiated species (LiN-5 or LiN-6) and the lithium amide in thereaction mixture. The protonation of the lithium amide then hinders theisomerization of the 1,4-diene to the 1,3-diene, slowing the formationof the monoolefin. Potential effects of t-butoxide would warrant furtherinvestigation.

Also, literature has shown that more acidic alcohols (methanol, ethanol)give faster reductions but lower yields than bulkier alcohols(isopropanol, t-butanol) because of an off reaction with lithium tocreate H₂ (See, e.g., Krapcho, A. P. et al. Kinetics of themetal-ammonia-alcohol reductions of benzene and substituted benzenes. J.Am. Chem. Soc., 1959, 81, 3658-3666 and Shabangi, R. A. et al.Electrochemical investigation of the reducing power of SmI₂ in THF andthe effect of HMPA cosolvent. Tetrahedron Lett., 1997, 38, 1137-1140).Although the data mostly support such a notion, we wish to considerother factors based on the data with trifluoroethanol (52%), methanol(33%), and ethanol (58%) combined with the structural requirements ofthe amine, including optimal bite angle (ethylenediamine vs1,2-diamino-2-methypropane). For example, the equilibrium between amonomer and higher-order aggregates of various ligated lithiumintermediates can be affected by the amine ligand, among other factors.

The switch of the solvent from an amine to an ethereal solvent (THF) wasessential for this work. Ammonia gas in a balloon, lithium, and THFconditions (Altundas, A. et al. Excellent and convenient procedures forreduction of benzene and its derivatives. Turk. J. Chem., 2005, 29,513-518) suggests that the amine might not be needed as a solvent.1,2-Dimethoxyethane was ineffective as the solvent, indicating that onlyone molecule of THF binds to a lithium ion to form reactive species. Therole of THF as a ligand for the alkali metal ion most likely had notbeen considered before because the ethereal solvent was previously usedin smaller amounts than the amine solvent.

The method could reverse the chemoselectivity for the reduction ofPhCO₂H and ^(n)BuOPh by two orders of magnitude withtriethylenetetramine (61-fold difference under the standard Birchreduction conditions in favor of PhCO₂H and 2-fold difference under thepresent conditions in favor of ^(n)BuOPh). More broadly, thestructure-reactivity relationship indicates the potential for (reverse)chemoselective reduction in synthesis. To control the selectivity,inner- and outer-sphere electron transfer processes may be considered.It may also be suggested a broader role for the alcohol than previouslyconsidered, including the product selectivity with naphthalene andindole systems.

In addition to the theoretical advancements, the practicality of thetechnology should render the lithium-mediated reduction and deprotectionmore accessible to a broader scientific community and more amenable tothe time-economic synthesis of complex molecules. Finally, the scope ofthe Birch reduction may be expanded by combining the chemistry oforganolithium with other organometallic chemistry.

Detailed Reactions

Reagents

THF, ethylenediamine, and t-BuOH used in this study were not distilled.

General Procedure

Lithium wire was cut into approximately 1 cm pieces, and the pieces wereadded to the solution in portions over 2 min.

Specific Procedures

Reduction of benzoic acid to 1,4-dihydrobenzoic acid: The followingprocedure was performed for the reduction of benzoic acid to1,4-dihydrobenzoic acid:

A single-neck, 500-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Benzoic acid (5.00 g, 40.9 mmol), THF (140 mL), andethylenediamine (16.4 mL, 246 mmol, 6.0 equivalents) were added to theflask, and the resulting mixture was cooled to 0° C. while stirring.Lithium (852 mg, 123 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (35 min). Cold water (50mL) was added to the reaction mixture (CAUTION: Evolution of hydrogengas, for this reaction and many of the reactions below), and theresulting mixture was stirred until the remaining lithium was quenched.The resulting mixture was cooled with an ice bath and acidified withconcentrated HCl until pH=2. The mixture was concentrated under reducedpressure with a rotary evaporator until most THF was removed. Theresulting mixture was poured to a 125-mL separatory funnel, and theproduct was extracted with Et₂O (50 mL×3). The organic extracts werecombined, dried over Na₂SO₄, filtered through cotton, and concentratedunder reduced pressure to give 1,4-dihydrobenzoic acid as a pale-yellowoil (4.82 g, 95% yield).

Data for 1,4-dihydrobenzoic acid: ¹H NMR (300 MHz, CDCl₃, 294K) δ 11.52(br s, 1H, COOH), 5.93 (m, 2H, C₃—H), 5.83 (m, 2H, C₂—H), 3.78 (m, 1H,C₁—H), 2.70 (m, 2H, C₄—H). This data matches that known in the art (See,e.g., Ashtekar, K. D. Nucleophile-assisted alkene activation: Olefinsalone are often incompetent. J. Am. Chem. Soc., 2016, 138, 8114-8119).

Reduction of o-toluic acid to 2-methyl-2,5-cyclohexadiene-1-carboxylicacid: The following procedure was performed for the reduction ofo-toluic acid to 2-methyl-2,5-cyclohexadiene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. o-Toluic acid (1.00 g, 7.35 mmol), THF (24 mL), andethylenediamine (2.94 mL, 44.1 mmol, 6.0 equivalents) were added to theflask, and the resulting solution was stirred while cooling to 0° C.Lithium (153 mg, 22.0 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (30 min). Saturatedaqueous NH₄Cl (40 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was cooled with an ice bath and acidified withconcentrated HCl until pH=2. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting solid was determinedto be pure by ¹H NMR spectroscopy to give2-methyl-2,5-cyclohexadiene-1-carboxylic acid (971 mg, 97% yield) as awhite solid.

Data for 2-methyl-2,5-cyclohexadiene-1-carboxylic acid: ¹H NMR (300 MHz,CDCl₃, 294K) δ 11.57 (s, 1H), 5.95 (m, 1H), 5.77 (m, 1H), 5.67 (br s,1H), 3.64 (br q, 1H, J=3.9 Hz), 2.89-2.57 (m, 2H), 1.78 (s, 3H). Thisdata matches that known in the art (See, e.g., Rao, G. S. R. S.Synthesis based on cyclohexadienes. Part 8. Synthesis of1-methylbicyclo[2.2.2]oct-2-enecarboxylate derivatives. J. Chem. Soc.,Perkin Trans. 1, 1993, 2333-2337).

Reduction of 2,6-dimethylbenzoic acid to2,6-dimethyl-2,5-cyclohexadiene-1-carboxylic acid: The followingprocedure was performed for the reduction of 2,6-dimethylbenzoic acid to2,6-dimethyl-2,5-cyclohexadiene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2,6-Dimethylbenzoic acid (1.00 g, 6.66 mmol), THF (22 mL),and ethylenediamine (2.67 mL, 20.00 mmol, 6.0 equivalents) were added tothe flask, and the resulting solution was stirred while cooling to 0° C.Lithium (139 mg, 20.0 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (28 min). Saturatedaqueous NH₄Cl (40 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was cooled with an ice bath and acidified withconcentrated HCl until pH=2. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting solid was determinedto be pure by ¹H NMR spectroscopy to give2,6-dimethyl-2,5-cyclohexadiene-1-carboxylic acid (941 mg, 94% yield) asa white solid.

Data for 2,6-dimethyl-2,5-cyclohexadiene-1-carboxylic acid: ¹H NMR (300MHz, CDCl₃, 294K) δ 5.68 (br s, 2H), 3.48 (t, 1H, J=6.3 Hz), 2.88-2.56(m, 2H), 1.78 (s, 6H).

Reduction of 3,5-dimethylbenzoic acid to3,5-dimethyl-2,5-cyclohexadiene-1-carboxylic acid: The followingprocedure was performed for the reduction of 3,5-dimethylbenzoic acid to3,5-dimethyl-2,5-cyclohexadiene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 3,5-Dimethylbenzoic acid (1.00 g, 6.66 mmol), THF (22 mL),ethylenediamine (2.67 mL, 40.0 mmol, 6.0 equivalents), and1-methoxyadamantane (160 mg, 1.0 mmol, 0.1 equiv, internal standard)were added to the flask, and the resulting solution was stirred whilecooling to 0° C. Lithium (139 mg, 20.0 mmol, 3.0 equivalents) was addedto the solution. The reaction mixture was stirred at 0° C. (externaltemperature) until TLC analysis showed the reaction to be complete (45min). Saturated aqueous NH₄Cl (40 mL) was added to reaction mixture, andthe resulting mixture was stirred until the remaining lithium wasquenched. The resulting mixture was cooled with an ice bath andacidified with concentrated HCl until pH=2. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator until mostTHF was removed. The resulting mixture was poured to a 125-mL separatoryfunnel, and the product was extracted with Et₂O (30 mL×3). The organicextracts were combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting solid was determinedto be pure by ¹H NMR spectroscopy to give3,5-dimethyl-2,5-cyclohexadiene-1-carboxylic acid (911 mg, 90% yield) asa white solid.

Data for 3,5-dimethyl-2,5-cyclohexadiene-1-carboxylic acid: ¹H NMR (300MHz, CDCl₃, 294K) δ 5.53 (br s, 2H), 3.77 (m, 1H), 2.50 (br t, 2H, J=6.9Hz), 1.75 (s, 6H). This data matches that known in the art (See, e.g.,Bykova, T. et al. Multicomponent reactions of methyl substituted all-cistetrafluorocyclohexane aldehydes. Org. Biomol. Chem., 2016, 14,1117-1123).

Reduction of o-anisic acid to 2-methoxy-2,5-cyclohexadiene-1-carboxylicacid: The following procedure was performed for the reduction ofo-anisic acid to 2-methoxy-2,5-cyclohexadiene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. o-Anisic acid (1.00 g, 6.57 mmol), THF (22 mL), andethylenediamine (2.63 mL, 39.4 mmol, 6.0 equivalents) were added to theflask, and the resulting solution was stirred while cooling to 0° C.Lithium (137 mg, 19.7 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (41 min). Saturatedaqueous NH₄Cl (40 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was cooled with an ice bath and acidified withconcentrated HCl until pH=2. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (SiO₂, 5 to 20% EtOAc in hexanes with 1%acetic acid) to give 2-methoxy-2,5-cyclohexadiene-1-carboxylic acid (341mg, 34% yield) as a white solid.

Data for give 2-methoxy-2,5-cyclohexadiene-1-carboxylic acid: R_(f)=0.23(1% AcOH and 40% EtOAc in hexanes stained with I₂); ¹H NMR (500 MHz,CDCl₃, 296K) δ 10.47 (br s, 1H, COOH), 5.93 (m, 1H, C₆—H), 5.73 (dddd,1H, J=9.8, 4.0, 2.5, 2.5 Hz, C₅—H), 4.88 (br t, 1H, J=4.0 Hz, C₃—H),3.81 (overlapping dddd, J=8.8, 6.6, 3.7, 2.5 Hz, 1H, C₁—H), 3.59 (s, 3H,OCH₃), 2.92 (ddddd, 1H, J=22.4, 8.8, 6.6, 3.7, 2.5 Hz, C₄—H), 2.81(ddddd, 1H, J=22.4, 8.8, 4.0, 3.7, 2.5 Hz, C_(4′)—H); ¹³C NMR (125 MHz,CDCl₃, 294K) δ 177.0, 149.9, 127.7, 121.0, 93.6, 54.4, 45.7, 26.3; IR(neat) 2893, 2824, 1708, 1684, 1651, 1211 cm⁻¹; HRMS (ESI-TOF) m/z for[M−H]⁻ C₈H₉O₃, calculated 153.05462, found 153.05467; m.p. 62-64° C.

Conversion of m-anisic acid to 5-oxo-2-cyclohexene-1-carboxylic acid:The following procedure was performed for the conversion of m-anisicacid to 5-oxo-2-cyclohexene-1-carboxylic acid:

The following procedure was performed for the reduction of Asingle-neck, 100-mL round-bottom flask was equipped with a magnetic stirbar and a septum equipped with a needle connected to a bubbler as a gasoutlet. m-Anisic acid (1.00 g, 6.57 mmol), THF (22 mL) andethylenediamine (2.57 mL, 39.4 mmol, 6.0 equivalents) were added to theflask, and the resulting solution was stirred while cooling to 0° C.Lithium (137 mg, 19.7 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (25 min). Saturatedaqueous NH₄Cl (40 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was cooled with an ice bath and acidified withconcentrated HCl until pH=2. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (SiO₂, 5 to 60% EtOAc in hexanes with 1%acetic acid) to give 5-oxo-2-cyclohexene-1-carboxylic acid (611 mg, 61%yield) as a white solid.

Data for 5-oxo-2-cyclohexene-1-carboxylic acid: R_(f)=0.28 (1% AcOH and60% EtOAc in hexanes stained with I₂); ¹H NMR (500 MHz, CDCl₃, 296K) δ9.82 (br s, 1H, COOH), 6.04 (dddd, J=9.9, 3.9, 1.7, 1.7 Hz, 1H, C₆—H),5.99 (dddd, 1H, J=9.9, 3.4, 3.2, 1.7 Hz, C₅—H), 3.63 (ddddd, 1H, J=8.2,6.2, 3.9, 2.0, 2.0 Hz, C₁—H), 3.00 (dddd, 1H, J=6.8, 2.0, 2.0, 2.0 Hz,C₄—H), 2.95-2.87 (m, 1H, C_(4′)—H), 2.78 (dd, 1H, J=15.3, 6.4 Hz, C₆—H),2.65 (dd, 1H, J=15.3, 6.4 Hz, C_(6′)—H); ¹³C NMR (125 MHz, CDCl₃, 294K)δ 206.9, 178.0, 127.6, 124.1, 42.3, 40.3, 39.0; IR (neat) 2993, 2824,1716, 1671 cm⁻¹; HRMS (ESI-TOF) m/z for [M+H]⁺ C₇H₉O₃, calculated141.05462, found 141.05457; melting point: 95-101° C.

Conversion of benzoic acid to 1-methyl-2,5-cyclohexadiene-1-carboxylicacid: The following procedure was performed for the conversion ofbenzoic acid to 1-methyl-2,5-cyclohexadiene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Benzoic acid (1.00 g, 8.19 mmol), THF (27.0 mL), andethylenediamine (3.28 mL, 49.1 mmol, 6.0 equivalents) were added to theflask, and the resulting mixture was cooled to 0° C. while stirring.Lithium (170 mg, 24.2 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) for 1h. The color of the reaction mixture changed from clear to yellow todeep green/blue to yellow. Mel (1.27 mL, 20.5 mmol, 2.5 equivalents) wasadded dropwise over 5 min to the reaction mixture. A white precipitatewas generated during the addition. The reaction mixture was cooled withan ice bath and acidified with concentrated HCl until pH=2. Theresulting mixture was concentrated under reduced pressure with a rotaryevaporator until most THF was removed. The resulting mixture was pouredto a 125-mL separatory funnel, and the product was extracted with Et₂O(50 mL×3). The organic extracts were combined, dried over Na₂SO₄,filtered through cotton, and concentrated under reduced pressure.1-Methoxyadamantane (0.119 g, 0.716 mmol) was added to the residue andthe yield of 1-methyl-2,5-cyclohexadiene-1-carboxylic acid in theresidue was determined to be 59% based on the external standard.

Data for of 1-methyl-2,5-cyclohexadiene-1-carboxylic acid: ¹H NMR (300MHz, CDCl₃, 294K) δ 5.86-5.73 (m, 4H), 2.67 (m, 2H), 1.37 (s, 3H). Thisdata matches that known in the art (See, e.g., Yoshimi, Y. et al.Hydroxide ion as electron source for photochemical Birch-type reductionand photohalogenation. Tetrahedron Lett., 2008, 49, 3400-3404).

Reduction of 1-naphthoic acid to 1,4-dihydronaphthalene-1-carboxylicacid: The following procedure was performed for the reduction of1-naphthoic acid to 1,4-dihydronaphthalene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 1-Naphthoic acid (1.00 g, 5.81 mmol), THF (19 mL),ethylenediamine (2.33 mL, 34.9 mmol, 6.0 equivalents), and1-methoxyadamantane (160 mg, 1.0 mmol, 0.1 equivalents, internalstandard) were added to the flask, and the resulting solution wasstirred while cooling to 0° C. Lithium (121 mg, 17.4 mmol, 3.0equivalents) was added to the solution. The reaction mixture was stirredat 0° C. (external temperature) until TLC analysis showed the reactionto be complete (29 min). Saturated aqueous NH₄Cl (40 mL) was added toreaction mixture, and the resulting mixture was stirred until theremaining lithium was quenched. The resulting mixture was cooled with anice bath and acidified with concentrated HCl until pH=2. The resultingmixture was concentrated under reduced pressure with a rotary evaporatoruntil most THF was removed. The resulting mixture was poured to a 125-mLseparatory funnel, and the product was extracted with Et₂O (30 mL×3).The organic extracts were combined, dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure. The yield of1,4-dihydronaphthalene-1-carboxylic acid in the residue was determinedto be 78% based on the internal standard.

Data for 1,4-dihydronaphthalene-1-carboxylic acid: ¹H NMR (300 MHz,CDCl₃, 294K) δ 7.31-7.12 (m, 4H), 6.18 (m, 1H), 5.98 (m, 1H), 4.42 (brq, 1H, J=6.4 Hz), 3.61-3.44 (m, 1H), 3.35 (dt, 1H, J=35.7, 6.4 Hz).

Reduction of 1-naphthoic acid to1,4,5,8-tetrahydronaphthalene-1-carboxylic acid: The following procedurewas performed for the reduction of 1-naphthoic acid to1,4,5,8-tetrahydronaphthalene-1-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 1-Naphthoic acid (1.00 g, 5.81 mmol), THF (19 mL),ethylenediamine (4.65 mL, 69.7 mmol, 12.0 equivalents), and t-BuOH (1.67mL, 17.4 mmol, 3.0 equivalents) were added to the flask, and theresulting solution was stirred while cooling to 0° C. Lithium (241 mg,34.9 mmol, 6.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (39 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wascooled with an ice bath and acidified with concentrated HCl until pH=2.The resulting mixture was concentrated under reduced pressure with arotary evaporator until most THF was removed. The resulting mixture waspoured to a 125-mL separatory funnel, and the product was extracted withEtOAc (30 mL×3). The organic extracts were combined, dried over Na₂SO₄,filtered through cotton, and concentrated under reduced pressure. Theresulting solid was purified by recrystallization (5% EtOAc in hexanes)to give 1,4,5,8-tetrahydronaphthalene-1-carboxylic acid (1.26 g, 72%yield) as a white solid.

Data for 1,4,5,8-tetrahydronaphthalene-1-carboxylic acid: R_(f)=0.27 (1%AcOH and 40% EtOAc in hexanes stained with I₂); ¹H NMR (300 MHz, CDCl₃,296K) δ 6.04-5.91 (m, 1H), 5.84-5.74 (m, 1H, C₆—H), 5.74-5.65 (m, 2H),3.58 (br d, 1H, J=4.0 Hz), 2.89-2.40 (m, 6H); ¹³C NMR (75 MHz, CDCl₃,294K) δ 178.7, 127.6, 127.3, 124.2, 123.8, 122.1, 120.7, 47.3, 31.0,30.9, 29.3; IR (neat) 3022, 2875, 2816, 1685 cm⁻¹; HRMS (ESI-TOF) m/zfor [M+H]+C₁₁H₁₃O₂, calculated 177.09101, found 177.09114; meltingpoint: 117-121° C.

Reduction of 2-naphthoic acid to1,2,3,4-tetrahydronaphthalene-2-carboxylic acid: The following procedurewas performed for the reduction of 2-naphthoic acid to1,2,3,4-tetrahydronaphthalene-2-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2-Naphthoic acid (1.00 g, 5.81 mmol), THF (19 mL),ethylenediamine (3.88 mL, 58.1 mmol, 10.0 equivalents), and1-methoxyadamantane (136 mg, 0.818 mmol, 0.1 equivalents, internalstandard) were added to the flask, and the resulting solution wasstirred while cooling to 0° C. Lithium (201 mg, 29.0 mmol, 5.0equivalents) was added to the solution. The reaction mixture was stirredat 0° C. (external temperature) until TLC analysis showed the reactionto be complete (33 min). Saturated aqueous NH₄Cl (40 mL) was added toreaction mixture, and the resulting mixture was stirred until theremaining lithium was quenched. The resulting mixture was cooled with anice bath and acidified with concentrated HCl until pH=2. The resultingmixture was concentrated under reduced pressure with a rotary evaporatoruntil most THF was removed. The resulting mixture was poured to a 125-mLseparatory funnel, and the product was extracted with Et₂O (30 mL×3).The organic extracts were combined, dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure. The yield of1,2,3,4-tetrahydronaphthalene-2-carboxylic acid in the residue wasdetermined to be 59% based on the internal standard.

Data for 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid: ¹H NMR (300MHz, CDCl₃, 294K) δ 7.15-7.04 (m, 4H), 3.07-2.95 (m, 2H), 2.94-2.73 (m,3H), 2.31-2.19 (m, 1H), 1.98-1.84 (m, 1H).

Reduction of 2-naphthoic acid to1,2,3,4,5,8-hexahydronaphthalene-2-carboxylic acid: The followingprocedure was performed for the reduction of 2-naphthoic acid to1,2,3,4,5,8-hexahydronaphthalene-2-carboxylic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2-Naphthoic acid (1.00 g, 5.81 mmol), THF (19 mL),ethylenediamine (6.20 mL, 93.0 mmol, 16 equivalents), t-BuOH (1.67 mL,17.4 mmol, 3.0 equivalents), and 1-methoxyadamantane (112 mg, 0.818mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (322mg, 46.5 mmol, 8.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (29 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wascooled with an ice bath and acidified with concentrated HCl until pH=2.The resulting mixture was concentrated under reduced pressure with arotary evaporator until most THF was removed. The resulting mixture waspoured to a 125-mL separatory funnel, and the product was extracted withEt₂O (30 mL×3). The organic extracts were combined, dried over Na₂SO₄,filtered through cotton, and concentrated under reduced pressure. Theyield of 1,2,3,4,5,8-hexahydronaphthalene-2-carboxylic acid in theresidue was determined to be 65% based on the internal standard.

Data for 1,2,3,4,5,8-hexahydronaphthalene-2-carboxylic acid: ¹H NMR (300MHz, CDCl₃, 294K) δ 5.71 (s, 2H), 2.62-2.46 (m, 4H), 2.18-1.92 (m, 7H).

Reduction of hydrocinnamic acid to 3-(1,4-cyclohexadien-1-yl)propanoicacid: The following procedure was performed for the reduction ofhydrocinnamic acid to 3-(1,4-cyclohexadien-1-yl)propanoic acid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Hydrocinnamic acid (1.00 g, 6.66 mmol), THF (22 mL),ethylenediamine (4.45 mL, 66.6 mmol, 10 equivalents), t-BuOH (1.27 mL,13.3 mmol, 2.0 equivalents), and 1-methoxyadamantane (148 mg, 0.890mmol) were added to the flask, and the resulting solution was stirredwhile cooling to 0° C. Lithium (231 mg, 33.3 mmol, 5.0 equivalents) wasadded to the solution. The reaction mixture was stirred at 0° C.(external temperature) until TLC analysis showed the reaction to becomplete (30 min). Saturated aqueous NH₄Cl (40 mL) was added to reactionmixture, and the resulting mixture was stirred until the remaininglithium was quenched. The resulting mixture was cooled with an ice bathand acidified with concentrated HCl until pH=2. The resulting mixturewas concentrated under reduced pressure with a rotary evaporator untilmost THF was removed. The resulting mixture was poured to a 125-mLseparatory funnel, and the product was extracted with Et₂O (30 mL×3).The organic extracts were combined, dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure. The yield of3-(1,4-cyclohexadien-1-yl)propanoic acid in the residue was determinedto be 72% based on the internal standard.

Data for 3-(1,4-cyclohexadien-1-yl)propanoic acid: ¹H NMR (300 MHz,CDCl₃, 294K) δ 5.70 (br s, 2H), 5.46 (br s, 1H), 2.73-2.56 (m, 4H),2.55-2.42 (m, 2H), 2.30 (t, 2H, J=7.6 Hz).

Reduction of N-(tert-butoxycarbonyl)-L-phenylalanine to(S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-cyclohexadien-1-yl)propanoicacid: The following procedure was performed for the reduction ofN-(tert-butoxycarbonyl)-L-phenylalanine to(S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-cyclohexadien-1-yl)propanoicacid:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. N-(tert-Butoxycarbonyl)-L-phenylalanine (1.00 g, 3.77 mmol),THF (13 mL), ethylenediamine (2.52 mL, 37.7 mmol, 10.0 equivalents), andt-BuOH (1.08 mL, 11.3 mmol, 3.0 equivalents) were added to the flask,and the resulting solution was stirred while cooling to 0° C. Lithium(131 mg, 18.9 mmol, 5.0 equivalents) was added to the solution. Thereaction mixture was stirred at 0° C. (external temperature) until TLCanalysis showed the reaction to be complete (30 min). Saturated aqueousNH₄Cl (40 mL) was added to reaction mixture, and the resulting mixturewas stirred until the remaining lithium was quenched. The resultingmixture was cooled with an ice bath and acidified with o-phosphoric aciduntil pH=3-4. The resulting mixture was concentrated under reducedpressure with a rotary evaporator until most THF was removed. Theresulting mixture was poured to a 125-mL separatory funnel, and theproduct was extracted with Et₂O (30 mL×3). The organic extracts werecombined, dried over Na₂SO₄, filtered through cotton, and concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography (SiO₂, 5 to 50% EtOAc in hexanes with 1% aceticacid) to give(S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-cyclohexadien-1-yl)propanoicacid (551 mg, 54% yield) as a viscous, colorless oil.

Data for(S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-cyclohexadien-1-yl)propanoicacid: R_(f)=0.47 (1% AcOH and 60% EtOAc in hexanes stained with I₂); ¹HNMR (400 MHz, CDCl₃, 294K) δ 5.74-5.64 (br t, 2H, J=12.3 Hz), 5.54 (brs, 1H), 4.92 (d, 1H, J=7.2 Hz), 4.44-4.29 (m, 1H), 2.78-2.49 (m, 4H),2.41-2.27 (m, 1H), 1.80-1.67 (m, 1H), 1.44 (s, 9H); ¹³C NMR (100 MHz,CDCl₃, 294K) δ 177.3, 155.7, 129.9, 128.6, 123.9, 123.4, 80.4, 51.6,40.1, 34.8, 28.5, 28.3; IR (neat) 3324, 3034, 2978, 2926, 1716, 1395,1163 cm⁻¹; HRMS (ESI-TOF) m/z for [M−H]⁻ C₁₄H₁₂O₄N, calcd 266.13868,found 266.13885.

Reduction of n-butoxybenzene to 1-butoxy-1,4-cyclohexadiene: Thefollowing procedure was performed for the reduction of n-butoxybenzeneto 1-butoxy-1,4-cyclohexadiene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. n-Butoxybenzene (4.50 g, 30.0 mmol), THF (26 mL),ethylenediamine (12.0 mL, 180 mmol, 6.0 equivalents), and t-BuOH (7.16mL, 75.0 mmol, 2.5 equivalents) were added to the flask, and theresulting solution was cooled to 0° C. while stirring. Lithium (624 mg,89.9 mmol, 3.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (30 min). Saturated aqueous NH₄Cl (40mL) was added to the reaction mixture, and the resulting mixture wasstirred until the remaining lithium was quenched. The resulting mixturewas concentrated under reduced pressure with a rotary evaporator untilmost THF was removed. The resulting mixture was poured to a 125-mLseparatory funnel, and the product was extracted with Et₂O (30 mL×3).The organic extracts were combined, dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography (SiO₂, 0.25 to 2% EtOAc inhexanes) to give 1-butoxy-1,4-cyclohexadiene (3.82 g, 85% yield) as acolorless oil.

Data for 1-butoxy-1,4-cyclohexadiene: R_(f)=0.51 (1% EtOAc in hexanes,I₂); ¹H NMR (300 MHz, CDCl₃, 294K) δ 5.68 (br t, 2H, J 11.5 Hz), 4.61(br s, 1H), 3.68 (t, 2H, J=6.5 Hz), 2.85-2.75 (m, 2H), 2.75-2.66 (m,2H), 1.65 (br quint, 2H, J=7.6 Hz), 1.42 (sextet, 2H, J=7.6 Hz), 0.94(t, 3H, J=7.5 Hz); ¹³C NMR (100 MHz, CDCl₃, 294K) δ 152.1, 124.6, 123.3,91.0, 65.9, 31.2, 28.7, 26.4, 19.4, 13.9; HRMS (ESI-TOF) m/z for [M+H]⁺C₁₀H₁₇O, calculated 153.12739, found 153.12743.

Reduction of 2-methylanisole to 1-methoxy-2-methyl-1,4-cyclohexadiene:The following procedure was performed for the reduction of2-methylanisole to 1-methoxy-2-methyl-1,4-cyclohexadiene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2-Methylanisole (1.00 g, 8.19 mmol), THF (27 mL),ethylenediamine (3.28 mL, 49.1 mmol, 6.0 equivalents), t-BuOH (1.96 mL,20.4 mmol, 2.5 equivalents), and 1-methoxyadamantane (166 mg, 0.998mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (170mg, 24.6 mmol, 2.5 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (20 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator and thewater bath at 25° C. until most THF was removed. The resulting mixturewas poured to a 125-mL separatory funnel, and the product was extractedwith Et₂O (30 mL×3). The organic extracts were combined, dried overNa₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield of 1-methoxy-2-methyl-1,4-cyclohexadiene in theresidue was determined to be 69% based on the internal standard.

Data for 1-methoxy-2-methyl-1,4-cyclohexadiene: ¹H NMR (300 MHz, CDCl₃,294K) δ 5.72-5.58 (m, 2H), 3.53 (s, 3H), 2.85-2.74 (m, 2H), 2.74-2.63(m, 2H), 1.64 (s, 3H).

Reduction of 3-methylanisole to 1-methoxy-5-methyl-1,4-cyclohexadiene:The following procedure was performed for the reduction of3-methylanisole to 1-methoxy-5-methyl-1,4-cyclohexadiene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 3-Methylanisole (1.00 g, 8.19 mmol), THF (27 mL),ethylenediamine (3.28 mL, 49.1 mmol, 6.0 equivalents), t-BuOH (1.96 mL,20.4 mmol, 2.5 equivalents), and 1-methoxyadamantane (166 mg, 0.998mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (170mg, 24.6 mmol, 2.5 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (20 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator and thewater bath at 25° C. until most THF was removed. The resulting mixturewas poured to a 125-mL separatory funnel, and the product was extractedwith Et₂O (30 mL×3). The organic extracts were combined, dried overNa₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield of 1-methoxy-5-methyl-1,4-cyclohexadiene in theresidue was determined to be 63% based on the internal standard.

Data for 1-methoxy-5-methyl-1,4-cyclohexadiene: ¹H NMR (300 MHz, CDCl₃,294K) δ 5.41 (br s, 1H), 4.64 (br s, 1H), 3.56 (s, 3H), 2.84-2.72 (m,2H), 2.61 (t, 2H, J=7.6 Hz), 1.70 (s, 3H).

Reduction of 4-methylanisole to 1-methoxy-4-methyl-1,4-cyclohexadiene:The following procedure was performed for the reduction of4-methylanisole to 1-methoxy-4-methyl-1,4-cyclohexadiene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 4-Methylanisole (1.00 g, 8.19 mmol), THF (27 mL),ethylenediamine (3.28 mL, 49.1 mmol, 6.0 equivalents), t-BuOH (1.96 mL,20.4 mmol, 2.5 equivalents), and 1-methoxyadamantane (166 mg, 0.998mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (170mg, 24.6 mmol, 2.5 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (20 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator and thewater bath at 25° C. until most THF was removed. The resulting mixturewas poured to a 125-mL separatory funnel, and the product was extractedwith Et₂O (30 mL×3). The organic extracts were combined, dried overNa₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield of 1-methoxy-4-methyl-1,4-cyclohexadiene in theresidue was determined to be 75% based on the internal standard.

Data for 1-methoxy-4-methyl-1,4-cyclohexadiene: ¹H NMR (300 MHz, CDCl₃,294K) δ 5.35 (br s, 1H), 4.61 (br s, 1H), 3.54 (s, 3H), 2.69 (br s, 4H),1.68 (s, 3H).

Conversion of p-cresol to t-butyldimethyl(p-tolyloxy)silane: Thefollowing procedure was performed for the conversion of p-cresol tot-butyldimethyl(p-tolyloxy)silane:

A single-neck, 1000-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a nitrogeninlet. p-cresol (10.0 g, 92.5 mmol), Et₃N (19.3 mL, 139 mmol, 1.5equivalents), DMAP (2.26 g, 18.5 mmol, 0.2 equivalents), and CH₂Cl₂ (300mL) were added to the flask. TBSCl (16.7 g, 111 mmol, 1.2 equivalents)was added to the solution, and the reaction mixture was stirred at 25°C. for 16 h. Water (100 mL) was added to reaction mixture. The resultingmixture was poured to a 500-mL separatory funnel. The layers wereseparated. The organic layer was washed with water (100 mL) and brine(100 mL). The organic extract was dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure. The residue wasdistilled under reduced pressure (˜10 mmHg, boiling point: 67° C.) togive a colorless oil. The resulting colorless oil was passed through aplug of silica gel, eluting with 10% EtOAc in hexanes. The resultingfiltrate was concentrated under reduced pressure with a rotaryevaporator to give t-butyldimethyl(p-tolyloxy)silane as a clear oil(14.6 g, 71% yield).

Data for t-butyldimethyl(p-tolyloxy)silane: ¹H NMR (300 MHz, CDCl₃,294K) δ 7.02 (d, 2H, J=8.1 Hz), 6.73 (dd, 2H, J=8.1, 1.7 Hz), 2.28 (s,3H), 0.98 (s, 9H), 0.18 (s, 6H).

Reduction of t-butyldimethyl(p-tolyloxy)silane tot-butyldimethyl((4-methyl-1,4-cyclohexadien-1-yl)oxy)silane: Thefollowing procedure was performed for the reduction oft-butyldimethyl(p-tolyloxy)silane tot-butyldimethyl((4-methyl-1,4-cyclohexadien-1-yl)oxy)silane:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. t-Butyldimethyl(p-tolyloxy)silane (1.00 g, 4.50 mmol), THF(15 mL), ethylenediamine (1.80 mL, 27.0 mmol, 6.0 equivalents), t-BuOH(1.08 mL, 11.2 mmol, 2.5 equivalents), and 1-methoxyadamantane (86.0 mg,0.450 mmol, 0.1 equivalents, internal standard) were added to the flask,and the resulting solution was stirred while cooling to 0° C. Lithium(94.0 mg, 13.5 mmol, 3.0 equivalents) was added to the solution. Thereaction mixture was stirred at 0° C. (external temperature) until TLCanalysis showed the reaction to be complete (20 min). Saturated aqueousNH₄Cl (40 mL) was added to reaction mixture, and the resulting mixturewas stirred until the remaining lithium was quenched. The resultingmixture was concentrated under reduced pressure with a rotary evaporatorand the water bath at 25° C. until most THF was removed. The resultingmixture was poured to a 125-mL separatory funnel, and the product wasextracted with Et₂O (30 mL×3). The organic extracts were combined, driedover Na₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield oft-butyldimethyl((4-methyl-1,4-cyclohexadien-1-yl)oxy)silane in theresidue was determined to be 75% based on the internal standard.

Data for of t-butyldimethyl((4-methyl-1,4-cyclohexadien-1-yl)oxy)silane:¹H NMR (300 MHz, CDCl₃, 294K) δ 5.33 (br s, 1H), 4.83 (br s, 1H), 2.64(br s, 4H), 1.67 (s, 3H) 0.92 (s, 9H), 0.14 (s, 6H).

The prior art demonstrates the industrial application of the reductionof t-butyldimethyl(p-tolyloxy)silane to formt-butyldimethyl((4-methyl-1,4-cyclohexadien-1-yl)oxy)silane in 74% yieldafter 16 hours in batch (See, for example, Peters, B. K. et al. Scalableand safe synthetic organic electroreduction inspired by Li-ion batterychemistry. Science, 2019, 363, 838-845). The current method produced thesame product on a similar scale in 75% yield after 30 minutes.

Reduction of 6-methoxy-1,2,3,4-tetra-hydronaphthalene to6-methoxy-1,2,3,4,5,8-hexahydronaphthalene: The following procedure wasperformed for the reduction of 6-methoxy-1,2,3,4-tetra-hydronaphthaleneto 6-methoxy-1,2,3,4,5,8-hexahydro naphthalene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 6-Methoxy-1,2,3,4-tetrahydronaphthalene (1.00 g, 6.16 mmol),THF (21 mL), ethylenediamine (2.47 mL, 37.0 mmol, 6.0 equivalents),t-BuOH (1.47 mL, 15.4 mmol, 2.5 equivalents), and 1-methoxyadamantane(136 mg, 0.818 mmol, 0.1 equivalents, internal standard) were added tothe flask, and the resulting solution was stirred while cooling to 0° C.Lithium (128 mg, 18.5 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (20 min). Saturatedaqueous NH₄Cl (40 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was concentrated under reduced pressure with a rotaryevaporator and the water bath at 25° C. until most THF was removed. Theresulting mixture was poured to a 125-mL separatory funnel, and theproduct was extracted with Et₂O (30 mL×3). The organic extracts werecombined, dried over Na₂SO₄, filtered through cotton, and concentratedunder reduced pressure. The yield of6-methoxy-1,2,3,4,5,8-hexahydronaphthalene in the residue was determinedto be 78% based on the internal standard.

Data for 6-methoxy-1,2,3,4,5,8-hexahydronaphthalene: ¹H NMR (300 MHz,CDCl₃, 294K) δ 4.65 (t, 1H, J=3.4 Hz), 3.55 (s, 3H), 2.72-2.62 (m, 2H),2.62-2.52 (m, 2H), 1.96-1.86 (m, 4H), 1.67-1.60 (m, 4H).

Reduction of 5-indanol to 5-methoxy-2,3-dihydro-1H-indene: The followingprocedure was performed for the reduction of 5-indanol to5-methoxy-2,3-dihydro-1H-indene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a nitrogeninlet. 5-Indanol (5.00 g, 37.2 mmol), K₂CO₃ (8.24 g, 59.6 mmol, 1.6equivalents), Mel (3.48 mL, 55.9 mmol, 1.5 equivalents), and DMF (28.0mL) were added to the flask. The resulting solution was heated to 55° C.(external temperature) and left to stir for 16 h. The reaction mixturewas cooled to room temperature, poured to a 250-mL separatory funnel,and diluted with Et₂O (60 mL) and water (80 mL). The layers wereseparated, and the aqueous solution was extracted with Et₂O (30 mL×2).The organic extracts were combined and washed with saturated aqueousNaHCO₃ (40 mL), 1M NaOH (40 mL), and water (40 mL). The organic extractswere dried over Na₂SO₄, filtered through cotton, and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography (SiO₂, 1 to 4% EtOAc in hexanes) to give5-methoxy-2,3-dihydro-1H-indene (5.61 g, 97% yield) as a colorless oil.

Data for 5-methoxy-2,3-dihydro-1H-indene: ¹H NMR (300 MHz, CDCl₃, 294K)δ 7.12 (d, 1H, J=8.2 Hz), 6.79 (br s, 1H), 6.69 (dd, 1H, J=8.2, 2.3 Hz),3.78 (s, 3H), 2.86 (overlap dt, 4H, J=13.7, 7.4 Hz), 2.07 (quint, 2H,J=7.4 Hz).

Reduction of 5-methoxy-2,3-dihydro-1H-indene to5-methoxy-2,3,4,7-tetrahydro-1H-indene: The following procedure wasperformed for the reduction of 5-methoxy-2,3-dihydro-1H-indene to5-methoxy-2,3,4,7-tetrahydro-1H-indene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 5-Methoxy-2,3-dihydro-1H-indene (1.00 g, 6.75 mmol), THF (22mL), ethylenediamine (2.70 mL, 40.5 mmol, 6.0 equivalents), t-BuOH (1.61mL, 16.9 mmol, 2.5 equivalents), and 1-methoxyadamantane (140 mg, 0.818mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (140mg, 20.2 mmol, 3.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (15 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator and thewater bath at 25° C. until most THF was removed. The resulting mixturewas poured to a 125-mL separatory funnel, and the product was extractedwith Et₂O (30 mL×3). The organic extracts were combined, dried overNa₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield of 5-methoxy-2,3,4,7-tetrahydro-1H-indene in theresidue was determined to be 81% based on the internal standard.

Data for 5-methoxy-2,3,4,7-tetrahydro-1H-indene: ¹H NMR (300 MHz, CDCl₃,294K) δ 4.68 (br s, 1H), 3.57 (s, 3H), 2.80-2.63 (m, 4H), 2.28 (br t,4H, J=7.4 Hz), 1.90 (br quint, 2H, J=7.4 Hz).

Reduction of dextromethorphan to(4bS,9S)-3-methoxy-11-methyl-4,5,6,7,8,8a,9,10-octahydro-1H-9,4b-(epiminoethano)phenanthrene:The following procedure was performed for the reduction ofdextromethorphan to(4bS,9S)-3-methoxy-11-methyl-4,5,6,7,8,8a,9,10-octahydro-1H-9,4b-(epiminoethano)phenanthrene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Dextromethorphan hydrobromide (1.00 g, 2.70 mmol), THF (9.0mL), ethylenediamine (1.80 mL, 27.0 mmol, 10 equivalents), t-BuOH (0.775mL, 8.16 mmol, 3.0 equivalents), and 1-methoxyadamantane (86.0 mg, 0.352mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (94.0mg, 13.5 mmol, 5.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) for 5 min. When TLCanalysis showed the reaction to be incomplete, the reaction mixture wasallowed to stir at 25° C. (external temperature) until TLC analysisshowed the reaction to be complete (35 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator until mostTHF was removed. The resulting mixture was poured to a 125-mL separatoryfunnel, and the product was extracted with Et₂O (30 mL×3). The organicextracts were combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The yield of(4bS,9S)-3-methoxy-11-methyl-4,5,6,7,8,8a,9,10-octahydro-1H-9,4b-(epiminoethano)phenanthrene in the residue was determined to be 54% based on theinternal standard.

Data for(4bS,9S)-3-methoxy-11-methyl-4,5,6,7,8,8a,9,10-octahydro-1H-9,4b-(epiminoethano)phenanthrene:¹H NMR (300 MHz, CDCl₃, 294K) δ 4.59 (br s, 1H), 3.53 (s, 3H), 2.77-2.66(m, 2H), 2.66-2.54 (m, 2H), 2.54-2.41 (m, 3H), 2.33 (s, 3H), 2.04 (dd,1H, J=18.2, 8.7 Hz), 1.89-1.85 (m, 2H), 1.71-1.65 (m, 2H), 1.59-1.52 (m,2H), 1.48-1.34 (m, 6H), 1.02 (dd, 1H, J=13.4, 3.2 Hz).

Reduction of estradiol 3-methyl ether to(8R,9S,13S,14S)-3-methoxy-13-methyl-4,6,7,8,9,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-ol:The following procedure was performed for the reduction of estradiol3-methyl ether to(8R,9S,13S,14S)-3-methoxy-13-methyl-4,6,7,8,9,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-ol:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Estradiol 3-methyl ether (0.980 g, 3.52 mmol), THF (12 mL),ethylenediamine (2.35 mL, 35.2 mmol, 10 equivalents), t-BuOH (1.01 mL,10.6 mmol, 3.0 equivalents), and 1-methoxyadamantane (86.0 mg, 0.352mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (122mg, 17.6 mmol, 5.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (30 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator until mostTHF was removed. The resulting mixture was poured to a 125-mL separatoryfunnel, and the product was extracted with Et₂O (30 mL×3). The organicextracts were combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The yield of(8R,9S,13S,14S)-3-methoxy-13-methyl-4,6,7,8,9,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-olin the residue was determined to be 56% based on the internal standard.

Data for(8R,9S,13S,14S)-3-methoxy-13-methyl-4,6,7,8,9,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-ol:¹H NMR (300 MHz, CDCl₃, 294K) δ 4.64 (br s, 1H), 3.68 (t, 1H, J=8.4 Hz),3.55 (s, 3H), 2.97-2.79 (m, 1H), 2.79-2.40 (m, 4H), 2.13-2.00 (m, 2H),2.00-1.79 (m, 3H), 1.77-1.56 (m, 3H), 1.55-1.00 (m, 8H), 0.77 (s, 3H).

Reduction of 2-(o-tolyl)ethanol to2-(2-methyl-1,4-cyclohexadien-1-yl)ethan-1-ol: The following procedurewas performed for the reduction of 2-(o-tolyl)ethanol to2-(2-methyl-1,4-cyclohexadien-1-yl)ethan-1-ol:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2-(o-Tolyl)ethanol (1.00 g, 7.34 mmol), THF (24 mL),ethylenediamine (4.90 mL, 73.4 mmol, 10 equivalents), t-BuOH (1.05 mL,11.0 mmol, 1.5 equivalents), and 1-methoxyadamantane (136 mg, 0.818mmol, 0.1 equivalents, internal standard) were added to the flask, andthe resulting solution was stirred while cooling to 0° C. Lithium (255mg, 36.7 mmol, 5.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (20 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator and thewater bath at 25° C. until most THF was removed. The resulting mixturewas poured to a 125-mL separatory funnel, and the product was extractedwith Et₂O (30 mL×3). The organic extracts were combined, dried overNa₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield of 2-(2-methyl-1,4-cyclohexadien-1-yl)ethan-1-ol inthe residue was determined to be 64% based on the internal standard.

Data for 2-(2-methyl-1,4-cyclohexadien-1-yl)ethan-1-ol: ¹H NMR (300 MHz,CDCl₃, 294K) δ 5.69 (br d, 2H, J=1.2 Hz), 3.67 (br t, 2H, J=6.8 Hz),2.70-2.57 (m, 4H), 2.35 (t, 2H, J=6.8 Hz), 1.69 (s, 3H).

Reduction of naphthalene to 1,4,5,8-tetrahydronaphthalene: The followingprocedure was performed for the reduction of naphthalene to1,4,5,8-tetrahydronaphthalene:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Naphthalene (1.00 g, 7.80 mmol), THF (26 mL),ethylenediamine (5.21 mL, 78.0 mmol, 10 equivalents), and t-BuOH (2.24mL, 23.4 mmol, 3.0 equivalents) were added to the flask, and theresulting solution was stirred while cooling to 0° C. Lithium (271 mg,39.0 mol, 5.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (33 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting solution wasstirred until the remaining lithium was quenched. The resulting mixturewas concentrated under reduced pressure with a rotary evaporator untilmost THF was removed. The resulting mixture was poured to a 125-mLseparatory funnel, and the product was extracted with Et₂O (30 mL×3).The organic extracts were combined, dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography (SiO₂, 5 to 10% EtOAc inhexanes) to give 1,4,5,8-tetrahydronaphthalene (966 mg, 96% yield) as acolorless solid.

Data for 1,4,5,8-tetrahydronaphthalene: ¹H NMR (300 MHz, CDCl₃, 294K) δ5.73 (s, 4H), 2.54 (s, 8H).

Reduction of benzylamine to 1,4-cyclohexadien-1-ylmethanamine: Thefollowing procedure was performed for the reduction of benzylamine to1,4-cyclohexadien-1-ylmethanamine:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Benzylamine (1.00 g, 9.33 mmol), THF (30 mL),ethylenediamine (3.74 mL, 56.0 mmol, 6.0 equivalents), and t-BuOH (1.34mL, 14.0 mmol, 1.5 equivalents) were added to the flask, and theresulting solution was stirred while cooling to 0° C. Lithium (194 mg,36.7 mmol, 3.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (26 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture (CAUTION: Evolution of hydrogen gas),and the resulting mixture was stirred until the remaining lithium wasquenched. The resulting mixture was concentrated under reduced pressurewith a rotary evaporator and the water bath at 25° C. until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The oil was determined to be pureby ¹H NMR spectroscopy to give 1,4-cyclohexadien-1-ylmethanamine (530mg, 52% yield) as a yellow oil.

Data for 1,4-cyclohexadien-1-ylmethanamine: R_(f)=0.35 (10% MeOH inCH₂Cl₂, I₂); ¹H NMR (400 MHz, CDCl₃, 294K) δ 5.79-5.63 (br s, 2H), 5.57(br s, 1H), 3.16 (s, 2H), 2.69 (app d, 2H, J=5.5 Hz), 2.63 (app d, 2H,J=9.9 Hz), 1.32 (br s, 2H); ¹³C NMR (100 MHz, CDCl₃, 294K) δ 136.4,124.3, 124.0, 117.8, 48.1, 27.4, 26.5; IR (neat) 3375, 3290, 3025, 2819,1428 cm⁻¹; HRMS (ESI-TOF) m/z for [M+H]⁺ C₇H₁₂N, calculated 110.0964,found 110.0966.

Reduction of benzylamine to 2-(1,4-cyclohexadien-1-yl)ethan-1-amine: Thefollowing procedure was performed for the reduction of benzylamine to2-(1,4-cyclohexadien-1-yl)ethan-1-amine:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Phenethylamine (1.00 g, 8.21 mmol), THF (27 mL),ethylenediamine (3.29 mL, 49.3 mmol, 6.0 equivalents), and t-BuOH (1.18mL, 12.3 mmol, 1.5 equivalents) were added to the flask, and theresulting solution was stirred while cooling to 0° C. Lithium (171 mg,24.6 mmol, 3.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (20 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture (CAUTION: Evolution of hydrogen gas),and the resulting mixture was stirred until the remaining lithium wasquenched. The resulting mixture was concentrated under reduced pressurewith a rotary evaporator and the water bath at 25° C. until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The oil was determined to be pureby ¹H NMR spectroscopy to give 2-(1,4-cyclohexadien-1-yl)ethan-1-amine(815 mg, 80% yield) as a yellow oil.

Data for 2-(1,4-cyclohexadien-1-yl)ethan-1-amine: R_(f)=0.53 (10% MeOHin CH₂Cl₂, I₂); ¹H NMR (400 MHz, CDCl₃, 294K) δ 5.70 (app t, 2H, J=11.9Hz), 5.48 (app s, 1H), 2.77 (t, 2H, J=6.8), 2.74-2.66 (m, 2H), 2.58 (appt, 2H, J=8.7 Hz), 2.11 (t, 2H, J=6.8 Hz), 1.28 (br s, 2H); ¹³C NMR (100MHz, CDCl₃, 294K) δ 132.4, 124.3, 124.2, 120.4, 41.6, 39.6, 28.7, 26.8;IR (neat) 3366, 3291, 3025, 2819, 1429 cm⁻¹; HRMS (ESI-TOF) m/z for[M+H]⁺ C₈H₁₄N, calculated 124.1121, found 124.1123.

Reduction of 4-methoxybenzylalcohol to(4-methoxy-1,4-cyclohexadien-1-yl)methanol: The following procedure wasperformed for the reduction of 4-methoxybenzylalcohol to(4-methoxy-1,4-cyclohexadien-1-yl)methanol:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 4-Methoxybenzylalcohol (1.00 g, 7.24 mmol), THF (24 mL),ethylenediamine (2.90 mL, 43.4 mmol, 6.0 equivalents), and t-BuOH (1.04mL, 10.9 mmol, 1.5 equivalents) were added to the flask, and theresulting solution was stirred while cooling to 0° C. Lithium (151 mg,21.7 mmol, 3.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (60 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture (CAUTION: Evolution of hydrogen gas),and the resulting mixture was stirred until the remaining lithium wasquenched. The resulting mixture was concentrated under reduced pressurewith a rotary evaporator and the water bath at 25° C. until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (SiO₂, 5 to 30% EtOAc in hexanes with 1%methanol) to give (4-methoxy-1,4-cyclohexadien-1-yl)methanol (548 mg,54% yield) as a clear oil.

Data for (4-methoxy-1,4-cyclohexadien-1-yl)methanol: R_(f)=0.35 (40%EtOAc in Hex, I₂); ¹H NMR (400 MHz, CDCl₃, 294K) δ 5.64 (app S, 1H),4.65 (app t, 1H, J=3.3 Hz), 4.01 (s, 2H), 3.54 (s, 3H), 2.83-2.76 (m,2H), 2.76-2.69 (m, 2H); ¹³C NMR (100 MHz, CDCl₃, 294K) δ 152.7, 135.3,119.1, 90.2, 66.4, 53.9, 28.8, 26.7; IR (neat) 3330, 2995, 2825, 1666,1214, 1075 cm⁻¹; HRMS (ESI-TOF) m/z for [M+H]⁺ C₈H₁₃O₂, calculated141.0910, found 141.0911.

Reduction of benzylalcohol to 1,4-cyclohexadien-1-ylmethanol: Thefollowing procedure was performed for the reduction of benzylalcohol to1,4-cyclohexadien-1-ylmethanol:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Benzyl alcohol (1.00 g, 9.25 mmol), THF (30 mL),ethylenediamine (4.94 mL, 74.0 mmol, 8.0 equivalents), t-BuOH (1.33 mL,13.9 mmol, 1.5 equivalents), and 1-methoxyadamantane (154 mg, 0.925mmol, 0.1 equivalents) were added to the flask, and the resultingsolution was stirred while cooling to 0° C. Lithium (257 mg, 37.0 mmol,4.0 equivalents) was added to the solution. The reaction mixture wasstirred at 0° C. (external temperature) until TLC analysis showed thereaction to be complete (40 min). Saturated aqueous NH₄Cl (40 mL) wasadded to reaction mixture (CAUTION: Evolution of hydrogen gas), and theresulting mixture was stirred until the remaining lithium was quenched.The resulting mixture was concentrated under reduced pressure with arotary evaporator and the water bath at 25° C. until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The yield of1,4-cyclohexadien-1-ylmethanol in the residue was determined to be 26%based on the internal standard.

Data for 1,4-cyclohexadien-1-ylmethanol: ¹H NMR (300 MHz, CDCl₃, 294K) δ5.75-5.72 (m, 1H), 5.72-5.64 (m, 2H) 4.00 (app s, 2H), 2.73-2.65 (m,4H).

Reduction of 1-methylindole to 1-methylindoline: The following procedurewas performed for the reduction of 1-methylindole to 1-methylindoline:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 1-Methylindole (1.00 g, 7.62 mmol), THF (25 mL), andethylenediamine (4.07 mL, 61.0 mmol, 8.0 equivalents) were added to theflask and the resulting solution was stirred while cooling to 0° C.Lithium (212 mg, 30.5 mmol, 4.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (28 min). Saturatedaqueous NH₄Cl (40 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was concentrated under reduced pressure with a rotaryevaporator until most THF was removed. The resulting mixture was pouredto a 125-mL separatory funnel, and the product was extracted with Et₂O(30 mL×3). The organic extracts were combined, dried over Na₂SO₄,filtered through cotton, and concentrated under reduced pressure. Theresulting yellow oil was determined to be pure by ¹H NMR spectroscopy togive 1-methylindoline (650 mg, 63% yield) as a yellow oil.

Data for 1-methylindoline: ¹H NMR (300 MHz, CDCl₃, 294K) δ 7.09 (m, 2H),6.67 (app br t, 1H, J=7.3 Hz), 6.49 (br d, 1H, J=7.9 Hz), 3.29 (t, 2H,J=8.2 Hz), 2.94 (t, 2H, J=8.2 Hz), 2.76 (s, 3H).

Reduction of 1-methylindole to 1-methyl-4,7-dihydro-1H-indole: Thefollowing procedure was performed for the reduction of 1-methylindole to1-methyl-4,7-dihydro-1H-indole:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 1-Methylindole (1.00 g, 7.62 mmol), THF (25 mL),ethylenediamine (4.07 mL, 61.0 mmol, 8.0 equivalents), and t-BuOH (2.19mL, 22.9 mmol, 3.0 equivalents) were added to the flask, and theresulting solution was stirred while cooling to 0° C. Lithium (212 mg,30.5 mmol, 4.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) until TLC analysisshowed the reaction to be complete (40 min). Saturated aqueous NH₄Cl (40mL) was added to reaction mixture, and the resulting mixture was stirreduntil the remaining lithium was quenched. The resulting mixture wasconcentrated under reduced pressure with a rotary evaporator until mostTHF was removed. The resulting mixture was poured to a 125-mL separatoryfunnel, and the product was extracted with Et₂O (30 mL×3). The organicextracts were combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. Mesitylene (93 mg, 0.773 mmol) wasadded to the residue. The yield of 1-methyl-4,7-dihydro-1H-indole wasdetermined to be 61% yield based on the external standard.

Data for 1-methyl-4,7-dihydro-1H-indole: ¹H NMR (300 MHz, CDCl₃, 294K) δ6.56 (d, 1H, J=2.3 Hz), 5.96 (d, 1H, J=2.3 Hz), 5.95-5.81 (m, 2H), 3.52(s, 3H), 3.37-3.17 (m, 4H).

Reduction of indole to 4,7-dihydro-1H-indole: The following procedurewas performed for the reduction of indole to 4,7-dihydro-1H-indole:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Indole (1.00 g, 8.54 mmol), THF (28 mL), ethylenediamine(4.56 mL, 68.3 mmol, 8.0 equivalents), and t-BuOH (2.45 mL, 25.6 mmol,3.0 equivalents) were added to the flask, and the resulting solution wasstirred while cooling to 0° C. Lithium (237 mg, 34.1 mmol, 4.0equivalents) was added to the solution. The reaction mixture was stirredat 0° C. (external temperature) until TLC analysis showed the reactionto be complete (40 min). Saturated aqueous NH₄Cl (40 mL) was added toreaction mixture, and the resulting mixture was stirred until theremaining lithium was quenched. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. Mesitylene (102 mg, 0.849 mmol) wasadded to the residue. The yield of 4,7-dihydro-1H-indole was determinedto be 60% yield based on the external standard.

Data for 4,7-dihydro-1H-indole: ¹H NMR (300 MHz, CDCl₃, 294K) δ 7.81 (brs, 1H), 6.72 (br s, 1H), 6.06 (d, 1H, J=2.3 Hz), 5.94 (br d, 1H, J=10.5Hz), 5.86 (br d, 1H, J=10.5 Hz), 3.29 (br s, 4H).

Reduction of acridine to 9,10-dihydroacridine: The following procedurewas performed for the reduction of acridine to 9,10-dihydroacridine:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Acridine (1.00 g, 5.58 mmol), THF (19 mL), ethylenediamine(2.23 mL, 33.5 mmol, 6.0 equivalents), and acetic acid (0.479 mL, 8.37mmol, 1.5 equivalents) were added to the flask, and the resultingsolution was stirred while cooling to 0° C. Lithium (120 mg, 17 mmol,3.0 equivalents) was added to the solution. The reaction mixture wasallowed to slowly warm to 25° C. until TLC analysis showed the reactionto be complete (5 h). Saturated aqueous NH₄Cl (40 mL) was added toreaction mixture, and the resulting mixture was stirred until theremaining lithium was quenched. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator until most THF wasremoved. The resulting mixture was poured to a 125-mL separatory funnel,and the product was extracted with Et₂O (30 mL×3). The organic extractswere combined, dried over Na₂SO₄, filtered through cotton, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (SiO₂, 2.5 to 10% EtOAc in hexanes) togive 9,10-dihydroacridine (905 mg, 90% yield) as a white solid.

Data for 9,10-dihydroacridine: ¹H NMR (300 MHz, CDCl₃, 294K) δ 7.08 (m,4H), 6.85 (td, 2H, J=7.4, 1.1 Hz), 6.66 (br d, 2H, J=7.4 Hz), 5.94 (s,1H), 4.05 (s, 2H).).

Conversion of 2,4,6-collidine to 3,5-dimethyl-2-cyclohexen-1-one: Thefollowing procedure was performed for the conversion of 2,4,6-collidineto 3,5-dimethyl-2-cyclohexen-1-one:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2,4,6-Collidine (1.00 g, 8.25 mmol), THF (28.0 mL), andethylenediamine (4.41 mL, 66.0 mmol, 8.0 equivalents) were added to theflask, and the resulting mixture was cooled to 0° C. while stirring.Lithium (229 mg, 33.0 mmol, 4.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) untilTLC analysis showed the reaction to be complete (60 min). During thistime, the reaction went from clear to yellow to deep blue to clearyellow. The reaction mixture was concentrated under reduced pressurewith a rotary evaporator until most THF was removed and kept under N₂.The resulting yellow residue was dissolved in EtOH (34 mL) under N₂.NaOH (990 mg, 24.8 mmol, 3.0 equivalents) was dissolved in water (20mL), and the resulting aqueous NaOH solution was added to the EtOHsolution. The reaction mixture was left to stir under an N₂ atmospherefor 2.5 h. The reaction mixture was acidified with concentrated HCl (15mL). The resulting mixture was poured to a 250-mL separatory funnel, andthe product was extracted with Et₂O (30 mL×3). The organic extracts werecombined, washed with saturated aqueous NaHCO₃ (30 mL×2) and brine (30mL). The resulting organic extracts were dried over Na₂SO₄, filteredthrough cotton, and concentrated under reduced pressure.1-Methoxyadamantane (0.158 g, 0.950 mmol) was added to the residue andthe yield of 3,5-dimethyl-2-cyclohexen-1-one in the residue wasdetermined to be 60% based on the external standard.

Data for 3,5-dimethyl-2-cyclohexen-1-one: ¹H NMR (400 MHz, CDCl₃, 294K)δ 5.86 (s, 1H), 2.40 (dd, 1H, J=16.5, 3.7 Hz), 2.28 (dd, 1H, J=16.5, 4.2Hz), 2.23-1.98 (m, 3H) 1.95 (s, 3H), 1.05 (d, 3H, J=6.5 Hz).

Conversion of 2,5-dihydrofuran to (Z)-2-buten-1-ol: The followingprocedure was performed for the reduction of 2,5-dihydrofuran to(Z)-2-buten-1-ol:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 2,5-Dihydrofuran (1.00 g, 14.3 mmol), THF (48 mL),ethylenediamine (4.76 mL, 71.3 mmol, 5 equivalents), and1-methoxyadamantane (273 mg, 1.43 mmol, 0.1 equivalents, internalstandard) were added to the flask, and the resulting solution wasstirred while cooling to 0° C. Lithium (248 mg, 35.7 mmol, 2.5equivalents) was added to the solution. The reaction mixture was stirredat 0° C. (external temperature) until TLC analysis showed the reactionto be complete (30 min). Saturated aqueous NH₄Cl (40 mL) was added toreaction mixture, and the resulting mixture was stirred until theremaining lithium was quenched. The resulting mixture was concentratedunder reduced pressure with a rotary evaporator and the water bath at25° C. until most THF was removed. The resulting mixture was poured to a125-mL separatory funnel, and the product was extracted with Et₂O (30mL×3). The organic extracts were combined, washed with brine, dried overNa₂SO₄, filtered through cotton, and concentrated under reduced pressureand the water bath at 25° C. until most THF was removed. The yield of(Z)-2-buten-1-ol in the residue was determined to be 41% based on theinternal standard.

Data for (Z)-2-buten-1-ol: ¹H NMR (300 MHz, CDCl₃, 294K) δ 5.67-5.51 (m,2H), 4.25-4.10 (m, 2H), 1.65 (d, 3H, J=4.5 Hz).

Conversion of octadecylamine to 4-methyl-N-octadecylbenzenesulfonamide:The following procedure was performed for the conversion ofoctadecylamine to 4-methyl-N-octadecylbenzenesulfonamide:

A single-neck, 250-mL round-bottom as was equipped with a magnetic stirbar and a septum equipped with a needle connected to a nitrogen inlet.1-Octadecylamine (5.00 g, 18.6 mmol) was dissolved in CH₂Cl₂ (62 mL)under N₂. p-Toluenesulfonyl chloride (3.89 g, 20.4 mmol, 1.1equivalents) and Et₃N (6.47 mL, 46.4 mmol, 2.5 equivalents) were addedto the solution. The reaction mixture was stirred at 24° C. for 19 h. A4 M aqueous solution of HCl (80 mL) was added to the reaction mixture,and the resulting solution was poured to a 250-mL separatory funnel. Thelayers were separated, and the aqueous layer was extracted with CH₂Cl₂(50 mL×2). The organic extracts were combined, dried over Na₂SO₄,filtered through cotton, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography (SiO₂, 2.5to 50% EtOAc in hexanes) to give 4-methyl-N-octadecylbenzenesulfonamide(7.00 g, 89% yield) as a white solid.

Data for 4-methyl-N-octadecylbenzenesulfonamide: R_(f)=0.23 (10% EtOAcin hexanes); ¹H NMR (300 MHz, CDCl₃, 294K) δ 7.75 (d, 2H, J=8.3 Hz),7.31 (d, 2H, J=8.3 Hz), 4.26 (t, 1H, J=6.0 Hz), 2.93 (q, 2H, J=6.8 Hz),2.43 (s, 3H), 1.44 (quint, 2H, J=6.8 Hz), 1.34-1.14 (m, 29H), 0.88 (t,3H, J=6.8 Hz); ¹³C NMR (75 MHz, CDCl₃, 294K) δ 143.3, 137.0, 129.7,127.1, 77.2, 50.0, 49.7, 49.4, 43.1, 42.0, 31.9, 29.7, 29.64, 29.61,29.5, 29.4, 29.3, 29.1, 26.5, 22.7, 21.5, 14.1; IR (neat) 3286, 2914,2848, 1328, 1157, 812, 669 cm⁻¹; HRMS (ESI-TOF) m/z for [M+H]⁺C₂₅H₄₆O₂NS, calcd 424.32438, found 424.32241.

Conversion of 4-methyl-N-octadecylbenzenesulfonamide to1-octadecanamine: The following procedure was performed for theconversion of 4-methyl-N-octadecylbenzenesulfonamide to1-octadecanamine:

A single-neck, 100-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. 4-Methyl-N-octadecylbenzenesulfonamide (1.00 g, 2.36 mmol),THF (8 mL), ethylenediamine (2.21 mL, 33.0 mmol, 14 equivalents), and1-methoxyadamantane (63.0 mg, 0.236 mmol, 0.1 equiv, internal standard)were added to the flask, and the resulting solution was stirred whilecooling to 0° C. Lithium (115 mg, 16.5 mmol, 7.0 equivalents) was addedto the solution. The reaction mixture was stirred at 0° C. (externaltemperature) until TLC analysis showed the reaction to be complete (31min). Water (30 mL) was added to reaction mixture, and the resultingmixture was stirred until the remaining lithium was quenched. Theresulting mixture was concentrated under reduced pressure with a rotaryevaporator until most THF was removed. The resulting mixture was pouredto a 125-mL separatory funnel, and the product was extracted with Et₂O(30 mL×3). The organic extracts were combined, washed with brine, driedover Na₂SO₄, filtered through cotton, and concentrated under reducedpressure. The yield of 1-octadecylamine in the residue was determined tobe 100% based on the internal standard.

Data for 1-octadecylamine: ¹H NMR (300 MHz, CDCl₃, 294K) δ 2.64 (t, 2H,J=7.5 Hz), 1.46-1.36 (m, 2H), 1.33-1.16 (m, 29H), 0.86 (t, 3H, J=7.5Hz).

Preparation of a mixture of trans-N-benzylpilolactam andcis-N-benzylpilolactam and subsequent debenzylation: The followingprocedure was performed for the preparation of a mixture oftrans-N-benzylpilolactam and cis-N-benzylpilolactam and subsequentdebenzylation:

A single-neck, 50-mL round-bottom flask was equipped with a magneticstir bar, a reflux condenser, and a septum equipped with a needleconnected to a nitrogen inlet. Pilocarpine hydrochloride (4.00 g, 16.4mmol) was dissolved in benzylamine (12.5 mL, 114 mmol, 7 equivalents)under N₂, and the resulting solution was heated to reflux for 72 h witha sand bath. The reaction mixture was cooled to room temperature anddiluted with 3 M NaOH (15 mL). The resulting solution was poured to a125-mL separatory funnel, and the layers were separated. The aqueoussolution was extracted with CH₂Cl₂ (30 mL×3). The organic extracts werecombined, washed with water (50 mL×2), dried over Na₂SO₄, filteredthrough cotton, and concentrated under reduced pressure. The benzylaminewas distilled under reduced pressure (5 mmHg, boiling point: 63° C.).The resulting residue was purified by flash column chromatography (SiO₂,5 to 100% EtOAc in hexanes to 5 to 50% MeOH in EtOAc) to give a mixtureof trans-N-benzylpilolactam and cis-N-benzylpilolactam (2.84 g, 58%yield) as an orange oil.

Reduction of(3R,4R)-1-benzyl-3-ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)pyrrolidin-2-oneto5-(((3R,4R)-4-ethyl-5-oxopyrrolidin-3-yl)methyl)-1-methyl-1H-imidazol-3-ium4-methylbenzenesulfonate: The following procedure was performed for thereduction of(3R,4R)-1-benzyl-3-ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)pyrrolidin-2-oneto5-(((3R,4R)-4-ethyl-5-oxopyrrolidin-3-yl)methyl)-1-methyl-1H-imidazol-3-ium4-methylbenzenesulfonate. A single-neck, 100-mL round-bottom flask wasequipped with a magnetic stir bar and a septum equipped with a needleconnected to a bubbler as a gas outlet.(3R,4R)-1-benzyl-3-ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)pyrrolidin-2-one(1.00 g, 3.36 mmol), THF (12 mL), and ethylenediamine (4.50 mL, 67.3mmol, 20 equivalents) were added to the flask, and the resultingsolution was stirred while cooling to 0° C. Lithium (233 mg, 33.6 mmol,10 equivalents) was added to the solution. The reaction mixture wasstirred at 0° C. (external temperature) until TLC analysis showed thereaction to be complete (45 min). Water (30 mL) was added to reactionmixture, and the resulting mixture was stirred until the remaininglithium was quenched. The resulting mixture was concentrated underreduced pressure with a rotary evaporator until most THF was removed.The resulting mixture was poured to a 125-mL separatory funnel, and thesolution was extracted with Et₂O (20 mL×2). The resulting organicextracts were discarded. The resulting aqueous solution was extractedwith CHCl₃ (20 mL×4). The resulting organic extracts were dried overNa₂SO₄, filtered through cotton, and concentrated under reducedpressure. The resulting residue was dissolved in acetone (6 mL) andfiltered through cotton into a 25-mL round-bottom flask equipped with amagnetic stir bar and a septum connected to a nitrogen inlet, and theresulting solution was stirred while cooling to 0° C. under a nitrogenatmosphere. p-Toluenesulfonic acid monohydrate (0.95 g, 5.00 mmol) wasdissolved in acetone (3 mL), and added to the cooled solution of residuedropwise over 15 min. When addition was complete, the resulting mixturewas stirred for an additional 20 min at 0° C. The resulting mixture wasfiltered through paper, washing the solid with cold acetone, dried underair atmosphere at 25° C., and then dried further under high vacuum. TheNMR of the white solid was shown to be pure5-(((3R,4R)-4-ethyl-5-oxopyrrolidin-3-yl)methyl)-1-methyl-1H-imidazol-3-ium4-methylbenzenesulfonate (410 mg, 32%).

Data for5-(((3R,4R)-4-ethyl-5-oxopyrrolidin-3-yl)methyl)-1-methyl-1H-imidazol-3-ium4-methylbenzenesulfonate: ¹H NMR (300 MHz, DMSO-d₆, 294K) δ 14.02 (br s,1H), 9.00 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.49 (d, 2H, J=8.0 Hz),7.12 (d, 2H, J=8.0 Hz), 3.78 (s, 3H), 3.33 (br t, 1H, J=8.5 Hz),2.96-2.69 (m, 3H), 2.47-2.36 (m, 1H), 2.29 (s, 3H), 2.00 (br q, 1H,J=6.0 Hz), 1.63-1.45 (m, 2H), 0.88 (t, 3H, J=7.5 Hz). 500-mmol scale:

Reduction of benzoic acid to 1,4-dihydrobenzoic acid: The followingprocedure was performed for the reduction of benzoic acid to1,4-dihydrobenzoic acid:

on a 500-mmol scale. A three-neck, 3-L round-bottom flask was equippedwith a mechanical stirrer, addition funnel, low-temperature thermometer,and a 3-way adaptor connected to a nitrogen inlet. The flask was cooledto 0° C., to which lithium (10.4 g, 1.50 mol, 3.0 equivalents) wasadded. The addition funnel was charged with THF (570 mL), and the THFwas slowly added to the lithium solid while cooling the suspension oflithium in THF to 0° C. (internal temperature) on an ice bath. Asolution of benzoic acid (61.10 g, 500 mmol) and ethylenediamine (200mL, 3.00 mol, 6.0 equivalents) in THF (260 mL) was prepared in aseparate Erlenmeyer flask and transferred to the addition funnel. Thesolution was then added to the suspension of lithium in THF over 16 minwhile keeping the internal temperature below 26° C. on an ice bath. Thereaction mixture was stirred at 10-26° C. (internal temperature) on anice bath until TLC analysis showed the reaction to be complete (15 min).Saturated aqueous NH₄Cl (500 mL) was slowly added to the reactionmixture over 8 min while keeping the internal temperature below 26° C.The resulting mixture was acidified with concentrated HCl until pH=2while keeping the internal temperature below 26° C. The mixture wasconcentrated under reduced pressure with a rotary evaporator until mostTHF was removed. The resulting mixture was poured to a 2000-mLseparatory funnel, and the product was extracted with Et₂O (200 mL×3).The organic extracts were combined, dried over Na₂SO₄, filtered throughcotton, and concentrated under reduced pressure to give1,4-dihydrobenzoic acid as a pale-yellow oil (59.6 g, 95% yield).

Data for 1,4-dihydrobenzoic acid: ¹H NMR (300 MHz, CDCl₃, 294K) δ 11.52(br s, 1H, COOH), 5.93 (m, 2H, C₃—H), 5.83 (m, 2H, C₂—H), 3.78 (m, 1H,C₁—H), 2.70 (m, 2H, C₄—H).

Reduction of benzoic acid to 1,4-dihydrobenzoic acid in presence ofn-butoxybenzene: The following procedure was performed for the reductionof benzoic acid to 1,4-dihydrobenzoic acid in presence ofn-butoxybenzene:

A 20-mL scintillation vial was equipped with a magnetic stir bar and aseptum equipped with a needle connected to a bubbler as a gas outlet.Benzoic acid (122 mg, 1.00 mmol), n-butoxybenzene (150 mg, 1.00 mmol),1-methoxyadamantane (33 mg, 0.200 mmol), THF (3 mL), and ethylenediamine(0.400 mL, 6.00 mmol, 6.0 equivalents) were added to the vial, and theresulting mixture was cooled to 0° C. while stirring. Lithium (17 mg,2.50 mmol, 2.5 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) for 1 h. Saturatedaqueous NH₄Cl (4 mL) was added to the reaction mixture, and theresulting mixture was stirred until the remaining lithium was quenched.The resulting mixture was concentrated under reduced pressure with arotary evaporator until most THF was removed. The resulting mixture wasextracted with Et₂O (6 mL×2). The organic extracts were combined andconcentrated under reduced pressure. The leftover aqueous solution wascooled with an ice bath and acidified with concentrated HCl until pH=2.The resulting mixture was extracted with Et₂O (6 mL×2). The organicextracts were combined, and concentrated (separately from the firstextraction) under reduced pressure. The yields of all components weredetermined from the internal standard.

Reduction of n-butoxybenzene to 1-butoxy-1,4-cyclohexadiene in presenceof benzoic acid: The following procedure was performed for the reductionof n-butoxybenzene to 1-butoxy-1,4-cyclohexadiene in presence of benzoicacid:

A 20-mL scintillation vial was equipped with a magnetic stir bar and aseptum equipped with a needle connected to a bubbler as a gas outlet.Benzoic acid (122 mg, 1.00 mmol), n-butoxybenzene (150 mg, 1.00 mmol),1-methoxyadamantane (33 mg, 0.200 mmol), THF (3 mL),triethylenetetramine (0.893 mL, 6.00 mmol, 6.0 equivalents), and t-BuOH(0.239 mL, 2.50 mmol, 2.5 equivalents) were added to the vial, and theresulting mixture was cooled to 0° C. while stirring. Lithium (21 mg,3.00 mmol, 3.0 equivalents) was added to the solution. The reactionmixture was stirred at 0° C. (external temperature) for 1 h. Saturatedaqueous NH₄Cl (4 mL) was added to the reaction mixture, and theresulting mixture was stirred until the remaining lithium was quenched.The resulting mixture was concentrated under reduced pressure with arotary evaporator until most THF was removed. The resulting mixture wasextracted with Et₂O (6 mL×2). The organic extracts were combined andconcentrated under reduced pressure. The leftover aqueous solution wascooled with an ice bath and acidified with concentrated HCl until pH=2.The resulting mixture was extracted with Et₂O (6 mL×2). The organicextracts were combined, and concentrated (separately from the firstextraction) under reduced pressure. The yields of all components weredetermined from the internal standard.

Conversion of benzoic acid to methyl1-(3-oxobutyl)-2,5-cyclohexadiene-1-carboxylate: The following procedurewas performed for the conversion of benzoic acid to methyl1-(3-oxobutyl)-2,5-cyclohexadiene-1-carboxylate:

A single-neck, 25-mL round-bottom flask was equipped with a magneticstir bar and a septum equipped with a needle connected to a bubbler as agas outlet. Benzoic acid (200 mg, 1.64 mmol), THF (5.00 mL), andethylenediamine (0.656 mL, 9.83 mmol, 6.0 equivalents) were added to theflask, and the resulting mixture was cooled to 0° C. while stirring.Lithium (34 mg, 24.2 mmol, 3.0 equivalents) was added to the solution.The reaction mixture was stirred at 0° C. (external temperature) for 1h. The color of the reaction mixture changed from clear to yellow todeep green/blue to yellow. CuI (3.12 g, 16.4 mmol, 10 equivalents) wasadded to the reaction mixture then 3-buten-2-one (1.36 mL, 16.4 mmol, 10equivalents) was added dropwise over 5 min to the reaction mixture. Thereaction mixture was allowed to slowly warm to 23° C. over 1.5 h withcontinued stirring. The reaction mixture was quenched with saturatedaqueous NH₄Cl (5 mL) and acidified with concentrated HCl until pH=2. Theresulting mixture was concentrated under reduced pressure with a rotaryevaporator until most THF was removed. The resulting mixture was dilutedwith H₂O (5 mL) and Et₂O (10 mL), and the resulting mixture was filteredthrough celite, washing the cake with Et₂O (10 mL). The resultingfiltrate was filtered through celite a second time due to an emulsion,further washing the cake with Et₂O (10 mL). The resulting mixture waspoured to a 60-mL separatory funnel, and the product was extracted withEt₂O (10 mL×4). The organic extracts were combined, dried over Na₂SO₄,filtered through cotton, and concentrated under reduced pressure to givea yellow oil residue. A single neck, 25-mL round-bottom flask wasequipped with a magnetic stir bar and a septum equipped with a needleconnected to a nitrogen inlet. The resulting residue was dissolved inEt₂O (5 mL) and placed in the pre-equipped round-bottom flask under N₂.The resulting mixture was cooled to 0° C. while stirring.(Trimethylsilyl)-diazomethane (0.820 mL, 1.37 mmol, 1 equivalents, 2M)was added to the reaction mixture dropwise over 1 minute. The reactionmixture was allowed to stir at 24° C. for 1.5 h and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography (SiO₂, 5 to 40% EtOAc in hexanes) to give methyl1-(3-oxobutyl)-2,5-cyclohexadiene-1-carboxylate (67.0 mg, 20% yield) asa yellow oil.

Data for methyl 1-(3-oxobutyl)-2,5-cyclohexadiene-1-carboxylate:R_(f)=0.19 (20% EtOAc in hexanes stained with 12, KMnO₄); ¹H NMR (500MHz, CDCl₃, 294K) δ 5.95-5.90 (app dt, 2H, J=10.4, 3.5 Hz), 5.71-5.65(dt, 2H, J=10.5, 2.0 Hz), 3.70 (s, 3H), 2.69-2.63 (mult, 2H), 2.36 (t,2H, J=8.5 Hz), 2.12 (s, 3H), 2.01-1.95 (t, 2H, J=8.5 Hz); ¹³C NMR (125MHz, CDCl₃, 294K) δ 208.2, 174.8, 126.6, 126.5, 123.9, 52.3, 47.2, 38.7,32.6, 30.1, 26.1; IR (neat) 3031, 2952, 1715, 1670, 1229 cm⁻¹; HRMS(ESI-TOF) m/z for [M+H]⁺ C₁₂H₂₇O₃, calculated 209.11722, found209.11723.

Having described this invention, it will be understood to those ofordinary skill in the art that the same can be performed within a wideand equivalent range of conditions, formulations and other parameterswithout affecting the scope of the invention or any embodiment thereof.

The invention claimed is:
 1. A method of reducing an aromatic ring orcyclic, allylic ether in a compound, comprising: preparing a reactionmixture comprising a compound comprising an aromatic moiety or a cyclic,allylic ether moiety, an alkali metal, and either ethylenediamine,diethylenetriamine, thiethylenetetramine, or a combination thereof, inan ether solvent, wherein the ethylenediamine:compound molar ratio orthe diethylenetriamine:compound molar ratio in the reaction mixtureranges from 2-20:1; and reacting the reaction mixture at a temperatureranging from −20° C. to 30° C. for a time sufficient to reduce a doublebond in the aromatic moiety to a single bond or to reduce the cyclic,allylic ether moiety.
 2. The method of claim 1, wherein the aromaticmoiety or cyclic, allylic ether moiety is substituted with a C₁-C₆carboxylic acid selected from carboxyl, carboxymethyl, carboxyethyl,carboxypropyl, carboxybutyl, carboxypentyl, or carboxyhexyl, includingstructural isomers thereof.
 3. The method of claim 1, wherein the alkalimetal is Li.
 4. The method of claim 1, wherein the aromatic moiety is aphenyl moiety or a fused benzene ring of a polycyclic aromatic moiety.5. The method of claim 1, wherein the aromatic moiety is a C₆-aryl or asubstituted C₆-aryl.
 6. The method of claim 1, wherein the aromaticmoiety is substituted with a C₁-C₆ carboxylic acid.
 7. The method ofclaim 1, wherein the aromatic moiety is substituted with a C₁-C₆ alkoxylgroup.
 8. The method of claim 1, wherein the aromatic moiety issubstituted with a carbonyl-substituted C₁-C₆ alkyl group or astructural isomer thereof.
 9. The method of claim 1, wherein thereaction is performed for a length of time sufficient to yield at least50% yield of the product of the conversion of the double bond in thearomatic moiety to a single bond.
 10. The method of claim 1, wherein thecompound is benzoic acid, a benzylic alcohol, or a benzylic amine. 11.The method of claim 1, wherein the ether solvent is a saturated cyclicether, or 1,4-dioxane, or a derivative thereof, wherein the derivativeoptionally can be alkyl-substituted or halo-substituted.
 12. The methodof claim 1, wherein the ethylenediamine:alkali metal molar ratio or thediethylenetriamine:alkali metal molar ratio is approximately or about2:1.
 13. The method of claim 1, wherein the reaction mixture is reactedat a temperature ranging from 0° C. to 10° C.
 14. The method of claim 1,wherein the compound comprises an aromatic moiety.
 15. The method ofclaim 1, wherein the compound comprises a cyclic, allylic ether moiety.